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  1. 1. REPRINTED FROM WWW.THYROIDMANAGER.ORG Chapter 14 – Thyroid Regulation and Dysfunction in the Pregnant Patient Daniel Glinoer, M.D., Ph.D Professor of Internal Medicine & Cheif of the Endocrine Division University Hospital Sant-Pierre - Universite Libre de Bruxelles, Brussels Belgium Updated August 2008 INTRODUCTION Over the past twenty years there has been a major expansion of our knowledge regarding thyroid disorders associated with pregnancy. These advances relate to the optimal management of pregnant women who are on l-thyroxine therapy, the impact of iodine deficiency on the mother and developing fetus, the adverse effects of maternal hypothyroidism on mental development in their offspring, thyroid dysfunction associated with postpartum thyroiditis, etc. Simultaneously, a doubling of the miscarriage rate has been reported in studies in antibody-positive euthyroid women, and an increase in preterm delivery has been found in women with subclinical hypothyroidism and/or thyroid autoimmunity. Given the rapidity of advances in this field, it is not surprising that some controversy surrounds the optimal detection and management of thyroid diseases during pregnancy, especially since pregnant women may have a variety of known or undisclosed thyroid conditions (such as hypothyroidism and hyperthyroidism), the presence of thyroid autoantibodies, thyroid nodules, or insufficient iodine nutrition. Pregnancy may affect the course of thyroid disorders and, conversely, thyroid diseases may affect the course of pregnancy. Moreover, thyroid disorders (and their management) may affect both the pregnant woman and the developing fetus. Finally, pregnant women may be under the care of multiple health care professionals, including obstetricians, nurse midwives, family practitioners, endocrinologists and/or internists, making the development of clinical practice guidelines all the more urgent and critical. Accordingly, an international task force was created under the auspices of the American Endocrine Society to review the best evidence in the field and develop evidence-based guidelines. Members of the task force included representatives from the Endocrine Society, American Thyroid Association (ATA), Association of American Clinical Endocrinologists (AACE), European Thyroid Association (ETA), Asia & Oceania Thyroid Association (AOTA), and the Latin American Thyroid Society (LATS). The task force worked for two years to develop the guidelines that were, eventually, approved by all the above-mentioned scientific international organizations. The task force finished its work in 2007. The guidelines were published in the Journal of Clinical Endocrinology and Metabolism (August 2007) as a Supplement containing the complete document and also in a shorter version or “Executive Summary” containing the main 35 recommendations agreed upon by the committee 1. MATERNAL THYROID PHYSIOLOGY Numerous hormonal changes and metabolic demands occur during pregnancy, resulting in profound and complex effects on thyroid function. As thyroid diseases are, in general, much more prevalent in women (than in men) during the childbearing period, it is not surprising that thyroid disorders such as chronic thyroiditis, hypothyroidism, Graves' disease, etc. are
  2. 2. relatively common in pregnant women. To facilitate our understanding of the pathologic processes that affect the thyroid gland, it is important to understand first the normal physiologic processes that take place in the pregnant state such as, for instance, changes in thyroid function tests, thyroid volume, immune modulation, thyroidal economy in relation with the iodine nutrition status, etc. Over the past fifteen to twenty years, a profusion of relevant new information regarding the relationships between pregnancy and the thyroid gland has allowed to clarify many aspects of the interactions between gestation and regulation of the thyroid system in normal individuals as well as patients with thyroid disorders. Despite these major new insights, many uncertainties remain and important questions remain incompletely elucidated. Finally, it is important to consider that the expecting mother is the natural carrier of a future child. Hence, understanding better the complex maternal-fetal interrelationships related to the ongoing thyroid processes must remain our constant quest, in order to ensure the best possible health status of mother and progeny. Regulation of the thyroid in normal pregnancy Table 14-1 summarizes the main physiologic changes that occur during a normal pregnancy, and which relate to thyroid function or thyroid function testing. Early in pregnancy there is an increase in renal blood flow and glomerular filtration which lead to an increase in iodide clearance from plasma 2-6. This results in a fall in plasma iodine concentrations and an increase in iodide requirements from the diet 2. In women with iodine sufficiency there is little thyroid impact of the obligatory increase in renal iodine losses, because the intrathyroidal iodine stores are plentiful at the time of conception and they remain unaltered throughout gestation. As an example, in a collaborative study between the Universities of Massachusetts (USA) and Santiago (Chili), iodine metabolism was investigated in the three trimesters of gestation and again after delivery. Plasma inorganic iodide (PII) concentrations, urinary iodide levels, and thyroid function tests were determined in 16 pregnant women. While the results showed a wide variability in PII values and urinary iodide concentrations, there was no trend for a decrease in PII concentrations during pregnancy. The conclusion was that pregnancy does not have a major influence on circulating iodine concentrations in iodine-sufficient regions. It should be noted, however, that the iodine excretion levels were unusually high in this study, ranging between 459-786 µg/day 7. Table 14-1. Factors affecting Thyroid Physiology during normal Pregnancy Physiologic Change Thyroid-related consequences Increased renal I- clearance Increased 24-hr RAIU Decreased plasma I- and placental I- In I- deficient women, decreased T4, transport to the fetus increased TSH, and goiter formation Increased O2 consumption by fetoplacental Increased BMR unit, gravid uterus and mother Increased free T4 and T3 First-trimester increase in hCG Decreased basal TSH (partial blunting of the pituitary-thyroid axis) Increased serum TBG Increased total T4 and T3 Increased plasma volume Increased T4 and T3 pool size Inner-ring deiodination of T4 and T3 by Accelerated rates of T4 and T3 degradation placenta and production In regions where the iodine supply is borderline or low, the situation is clearly different and significant changes occur during pregnancy 3, 4, 6. While 24-hour radioiodine uptake determinations are not usually performed in the pregnant state, past studies have shown that the uptake is increased 8. In addition, there is a further increment in iodine requirements, due to transplacental iodide transport necessary for iodothyronine synthesis by the fetal thyroid gland, which becomes progressively functional after the first trimester. Several
  3. 3. studies have convincingly documented the fact that, when pregnancy takes place in conditions with borderline iodine availability, significant increments in both maternal and fetal thyroid volume occur, when no supplemental iodine was given during early pregnancy 9-11. This is in sharp contrast with the notion that in iodine-sufficient areas, there is little, if any, change in thyroid size during pregnancy 12, 13. Effects of human chorionic gonadotropin on thyroid function Human chorionic gonadotropin (hCG) is a member of the glycoprotein hormone family that is composed of a common o -subunit and a non-covalently associated, hormone-spcific y - subunit. The -subunit of hCG consists of a polypeptide chain of 92 amino acid residues containing two N-linked oligosaccharide side-chains. The h -subunit of hCG consists of 145 residues with two N-linked and four O-linked oligosaccharide side-chains. The i -subunit of TSH is composed of 112 residues and one N-linked oligosaccharide. The n -subunits of both molecules possess 12 half-cysteine residues at highly conserved positions. Three disulfide bonds form a cystine knot structure, which is identical in both TSH and hCG and is essential for binding to their receptor (LH and hCG bind to the same receptor, the LHCG receptor). A single gene on chromosome 6 encodes for the common h -subunit, while the genes that encode for the c -subunits are clustered on chromosome 19, with seven genes (but only three actively transcribed) coding for -hCG 14-16. The structural homology between hCG and TSH provides already an indication that hCG may act as a thyrotropic agonist, by overlap of their natural functions. Human CG possesses an intrinsic (albeit weak) thyroid-stimulating activity and perhaps even a direct thyroid- growth-promoting activity 17-24. During normal pregnancy, the direct stimulatory effect of hCG on thyrocytes induces a small and transient increase in free thyroxine levels near the end of the 1st trimester (peak circulating hCG) and, in turn, a partial TSH suppression 3, 6, 25-31. When tested in bioassays, hCG is only about 1/104 as potent as TSH during normal pregnancy. This weak thyrotropic activity explains why, in normal conditions, the effects of hCG remain largely unnoticed and thyroid function tests mostly unaltered. The thyrotropic role of hCG in normal pregnancy is illustrated in Figure 14-1. The figure shows the inverse relationship between serum hCG and TSH concentrations, with a mirror image between the nadir of serum TSH and peak hCG levels et the end of the first trimester. The inset in the figure shows that the rise in serum free T4 is proportional to peak hCG values. At this period during gestation, 1/5th of otherwise euthyroid pregnant women have a transiently lowered serum TSH, even below the lower limit of the normal non pregnant reference range 3, 24, 32.
  4. 4. hCG vs. TSH Changes during Gestation 50 2.0 hCG 30 25 20 F ree T 4 40 p m o l/ L 15 10 1.5 20 40 60 80 100 hC G (I .U ./L x 1 0 0 0 ) 30 hCG 1.0 IU/Lx10 3 TSH 20 mIU/L 0.5 10 0.1 0 1st. Trimester 2nd. Trimester 3rd. Trimester weeks gestation 10 20 30 40 From: Glinoer et al. JCEM 71 : 276 (1990) Figure 1 The pattern of serum TSH and hCG changes are shown as a function of gestation age in 606 healthy pregnant women. Between 8 and 14 weeks gestation, changes in serum hCG and TSH are mirror images of each other, and there is a significant negative correlation between the individual TSH (nadir) and peak hCG levels (P<0.001) (hCG: ▲-----▲ ; TSH: ●-----●). The inset shows a scattergram of serum free T4 levels in the same women plotted in relation to circulating hCG concentrations (by 10.000 IU/L increment) during the first half of gestation. The figure shows the direct relationship between free T4 and hCG, with progressively increasing free T4 levels (from Glinoer, Ref 3). Experimental studies with desialylated and deglycosylated hCG, using T3 secretion as the response parameter (in a serum-free culture system with human thyroid follicles), have shown that removal of sialic acid or carbohydrate residues from native hCG transformed such hCG variants into thyroid stimulating super-agonists 33. Further evidence to support the patho-physiological role of hCG to stimulate excessively the human thyroid gland is can be found in studies of patients with hydatidiform mole and choriocarcinoma (see Chapter 13). In these conditions, clinical and biochemical manifestations of hyperthyroidism often occur and, as expected, the abnormal stimulation of the thyroid is rapidly relieved after appropriate surgical treatment 34-36. Hyperemesis gravidarum Vomiting occurs in normal pregnancy during the 1st trimester and ceases usually by the 15th week. Prolonged nausea and severe vomiting in early pregnancy that causes greater than a 5% weight loss, dehydration and ketonuria is defined as Hyperemesis Gravidarum (HG) and occurs in 0.5-10 cases per 1,000 pregnancies 37. Hyperemesis is associated with high hCG levels occurring at this time, but the exact cause remains uncertain. For unknown reasons, HG seems to be more prevalent in Asian than Caucasian women. Thirty to sixty percent of patients with HG have elevations of serum free thyroid hormone concentrations with a suppressed TSH 38. Women with hyperemesis and elevated thyroid hormone levels most commonly do not have other clinical evidence of primary thyroid disease, such as Graves’ disease. A minor proportion of these patients may have clinical hyperthyroidism, termed
  5. 5. ‘gestational hyperthyroidism’ or ‘gestational transient thyrotoxicosis’ (GTT). Obviously, Graves’ disease can also occur coincident with hyperemesis 39. Finally, many common signs and symptoms of hyperthyroidism may be mimicked by a normal pregnancy. The clinical challenge is therefore to differentiate between these two disorders 40-48. The etiology of excessive thyroid stimulation is considered to be hCG itself (or derivatives of hCG) via a direct stimulation of the thyroid cells through binding of hCG to the TSH receptor 49, 50. In virtually all patients with gestational hyperthyroidism, appropriate fluid replacement will lead to resolution of the clinical symptoms. As gestation proceeds and hCG levels progressively fall, normal thyroid function is resumed. In severe (but rare) cases, antithyroid drug treatment may be required (described in more detail below). Several investigators have observed that there may even be more subtle form of hyperthyroidism associated with morning sickness 41, 42, 46. Severity of emesis was correlated with serum free T4 and hCG levels (and inversely with the degree of TSH suppression), suggesting strongly that HG may reflect the extreme end of the spectrum of physiological changes that occur at this time in normal pregnancy (Figure 14-2). One tempting hypothesis to correlate conceptually the two is to consider that high hCG levels cause both an increased estrogen secretion as well as thyroid hyperfunction, and in turn explain the coexistence of nausea and vomiting with hyperthyroidism 45. hCG Free T4 TSH 140 4 3.0 120 2.5 3 100 2.0 80 3 IU/L x 10 ng/dL 2 mIU/L1.5 60 1.0 40 1 20 0.5 0 0 0.01 Non-Pregnant Reference Range TSH < 0. 2 mIU/L No Vom iting (n=3) Vom iting (n=27) 18% in 1st. Trim Hyperemesis (n=38) 5% in 2nd. Trim Severe Hyperemesis (n=19) 2% in 3rd. Trim Figure 2 Relationship between the severity of vomiting and the mean (with SE) serum concentrations of hCG, free T4, and TSH. The inset in the lower right part of the figure shows the prevalence of suppressed TSH levels, for each trimester of gestation, in a cohort of normal pregnant women. The data were graphically adapted by Carole Spencer (with my thanks to Carole for allowing me to borrow the slide). The figures are based on studies by Goodwin (Ref 42) & Glinoer (Ref 24). The charge-isoforms profiles of circulating hCG were investigated in women with hyperemesis gravidarum (HG) and different ethnic backgrounds (Samoan vs. European) 51. The results confirmed an increase in total serum hCG concentrations as well as an increase in the proportion of acidic hCG variants in the women suffering from HG, compared with
  6. 6. matched control subjects. The same study also confirmed the known association between hCG concentrations in early pregnancy and elevations in thyroid hormone levels 6.While there was no major association between HG and ethnic background, the authors observed a high prevalence of recurrent HG and a familial predisposition for this condition, suggesting that either long-term environmental factors or genetic factors may play a crucial role in the pathogenesis of HG and gestational transient non autoimmune thyrotoxicosis. Changes in circulating thyroid hormone binding proteins The increase in total serum T4 and T3 that occurs during pregnancy is due to an increase in serum thyroxine binding globulin (TBG) concentrations. Changes in TBG happen early and, by 16-20 weeks of gestation, TBG concentrations have doubled 3,6. The cause of the marked increase in serum TBG is probably multifactorial. Earlier studies showed that TBG biosynthesis was increased, after estradiol priming, in primary cultures of hepatocytes from Rhesus monkeys 52. However, the lack of increase in other binding proteins (CBG & SHBG) by estrogen in HEP-G2 cells raised the possibility that other factors might be operative in the pregnant state. Studies of changes in the glycosylation patterns of TBG, induced by estrogen, have indicated that the increase in circulating levels of TBG was due in large part to a reduction of its plasma clearance (see also Chapters 3, 5) 53. Sera of pregnant or estrogen-treated individuals show a marked increase in the more heavily sialylated fractions of TBG. This increase in the sialic acid content of TBG inhibits the uptake of the protein by specific asialylo-glycoprotein receptors on hepatocytes, and the more heavily sialylated proteins from pregnant sera have therefore a longer plasma half-life 54. Such alterations in sialylation are not found in TBG isolated from patients with congenital TBG elevation, the latter being due to a true over-production of the protein 55. Thus, in addition to the stimulatory estrogen effects of estrogen on TBG synthesis, a major contribution to the increased TBG concentration during pregnancy is the reduced clearance of the protein. This explanation is attractive since it would also also account for the increases observed in concentrations of other circulating glycoproteins in hyper-estrogenic states. Delivery leads to a rapid reversal of this process and serum TBG concentrations return to normal within 4-6 weeks. With that, serum T4 and T3 also return to pregestational serum levels. In addition to the 2 to 3-fold increase in serum TBG, modest decreases in both serum transthyretin (TTR) and albumin are commonly found in pregnancy, but the physiological impact of these changes, if any, is unknown 56. An interesting case report was published in 2003 57. A 42-year-old woman had both established hypothyroidism and inherited TBG deficiency, and was followed by the authors through 2 full-term pregnancies. The patient had a baseline TBG level that was approximately 70% below the average baseline level of non-TBG-deficient women. During her pregnancies, serum TBG levels rose, although remaining at only one half the usual increment in TBG associated with normal pregnancy. Despite the patient’s low baseline TBG level and blunted pregnancy-associated TBG rise, she required an increase in her thyroxine replacement doses that mirrored those observed in hypothyroid, but non-TBG-deficient pregnant women. The authors suggested therefore that an increase in TBG concentration was not the key determinant for the increase in thyroxine requirement in pregnancy. In a letter to the Editor, an alternative explanation was proposed 58. In the normal situation before pregnancy, the homeostasis of thyroid function is ensured by the equilibrium between a serum total T4 of ~100 nmol/L and a TBG concentration of ~260 nmol/L. This equilibrium implies, in turn, that ~75 % of the circulating T4 is bound to TBG and that ~35-40 % of circulating TBG is saturated by T4. During a normal pregnancy, the extracellular TBG pool expands from ~3,000 to ~7,000 nmol/L. Thus, for the homeostasis of free thyroid hormones to be maintained, the extra-thyroidal total thyroxine pool must parallel this expansion, and this can only be achieved by the thyroid gland filling up the progressively the increased hormonal pool during the first half of pregnancy (see Figure 14-3). In the exceptional case of Zigman, when this partially TBG-deficient patient was not pregnant, her serum total T4 was
  7. 7. ~70 nmol/L and TBG ~80 nmol/L, indicating that her circulating TBG was almost completely saturated by T4, because of her severe restriction in the TBG binding capacity. However in the non pregnant condition, only a relatively small fraction of the patient’s circulating T4 could be bound to TBG: ~50%. When the patient became pregnant, her TBG deficiency was still partially responsive to estrogen induction and TBG increased 3-fold to ~240 nmol/L and total T4 to ~90 nmol/L. In other words, her total T4 concentrations had to be raised by ~30% (via an increase in thyroxine replacement), hence allowing to restore a TBG binding saturation level by T4 of ~35%, equivalent to what is observed at the onset of pregnancy in non-TBG-deficient women. Thus, the increment required in l-T4 dosage was precisely of the same proportion than that anticipated from the partial rise in serum TBG during pregnancy. PRECONCEPTION Hyper E2 state STEADY STATE TBG extracellular pool : ~ 2,700 mMol Rapid expansion by 2.5 to 3-fold PREGNANCY STEADY STATE TBG extracellular pool : (up to 20 weeks) ~ 7,400 mMol
  8. 8. Extrathyroidal pool of T4 • In order to maintain normal ‘homeostatic’ serum free hormone levels, the extracellular TBG pool must steadily be filled with T4 • These changes take place in one trimester; hence the ‘extra-load’ on the glandular machinery • First month : + 30 % over baseline • Second month : + 45 % over baseline • Third month : + 60 % over baseline Together, this represents a 50 % increment above preconception thyroid hormone production Figure 3 The upper panel illustrates the rapid changes that occur in serum total binding capacity of TBG during the first half of gestation under the influence of elevated estrogen levels. The lower panel shows that, in order to maintain unaltered free T4 levels, the markedly increased TBG extra-cellular pool must steadily be filled with increasing amounts of T4, until a new equilibrium is reached. This is achieved during pregnancy via an overall ~50% increase in thyroid hormone production. Increased plasma volume The increased plasma concentration of TBG, together with the increased plasma volume, results in a corresponding increase in the total T4 pool during pregnancy. While the changes in TBG are most dramatic during the first trimester, the increase in plasma volume continues until delivery. Thus, for free T4 concentration to remain unaltered, the T4 production rate must increase (or its degradation rate decrease) to allow for additional T4 to accumulate. One would predict that in a situation where the T4 input was constant, there would be an iterative increment in T4 as TBG increases, due to reduced T4 availability to degradation enzymes. The evidence that thyroxine requirements are markedly enhanced during pregnancy in hypothyroid treated women (see section on maternal hypothyroidism) strongly suggests that not only T4 degradation is decreased in early pregnancy but also that an increased T4 production occurs throughout gestation to maintain the homeostasis of free T4 concentrations 6, 59-62. Thyroxine production rate The only direct measurements of T4 turnover rates in pregnancy were obtained more than 30 years ago by Dowling et al 63. In eight pregnant subjects (4 in 1st half & 4 in 2nd half of gestation), T4 turnover rates were estimated not to be significantly different from those of non-pregnant subjects. However, based on several considerations discussed above from more recent work, it can now be concluded that the T4 production rate is enhanced during
  9. 9. pregnancy. Globally, it is accepted that there is a ~50 % increase in the production of T4 during gestation 6, 64. Thyroid function parameters in normal pregnancy Total and free T4 and T3 As will be discussed in greater detail below, there is presently a controversy as to what type of thyroid hormone measurement represents the most reliable test to differentiate normal thyroid function from abnormalities associated with subtle thyroid dysfunction during pregnancy. The difficulties arise from 3 main facts: a) determinations of total T4 have progressively gone out of fashion (especially in Europe) and, when still used, the reference range for normal total T4 needs to be adapted to the pregnant state; b) the use of free T4 determinations encounters some technical difficulties (due to the assays used) that may sometimes hinder interpretation of results; and c) there are changes in the normal pattern of serum TSH during pregnancy that require correct interpretation of the data. Concerning total T4 determinations, the range of normal serum total T4 is modified during pregnancy under the influence of a rapid increase in serum TBG levels. The TBG plateau is reached at mid-gestation (see Figure 14-4, upper left panel) 3. If one uses total T4 to estimate thyroid function, it is therefore reasonable to adapt the non pregnant reference range (5-12 µg/dl; 50-150 nmol/L) by multiplying this range by 1.5 (i.e., 7.5-18 µg/dl; 75-225 nmol/L) during pregnancy. However, it should be noted that since total T4 values only reach a plateau around mid-gestation, such adaptation is only fully valid during the 2nd half of gestation (see Figure 14-4, upper right panel) 65-67. Thus, the use of total T4 still leaves the clinician in a quandary, since one wishes to be certain that a thyroid function is normal (or not) during earlier gestational stages. Concerning free T4 indirect estimates from total T4 determinations, a thyroid hormone binding ratio ‘THBR’ or free T4 index can be calculated 6, 26, 68. Because the reduction in the free T3 fraction is approximately equal to that of T4, the standard approach for these determinations (employing T3 as a tracer) can still be used. However, it is important to recognize that as the free fraction is reduced, the resin T3 uptake (and similar assessments of free hormone fractions) asymptotically approaches a fixed lower limit. This is not linearly related to the increase in unoccupied TBG binding sites. Thus, the decrease in the THBR does not usually match the quantitative decrease in the T4 and T3 free fractions estimated directly and in some sera, the free T4 index will end up being slightly elevated relative to the actual free T4 or free T3 concentration. Concerning direct serum free T4 measurements, the older ‘analogue’ technologies often resulted in a decreased free T4 estimate in strictly euthyroid pregnant subjects. These artifacts have been attributed to the influence of the physiologic serum albumin decrease which commonly occurs in pregnancy. Nowadays, many direct free T4 assays are routinely available, which provide more accurate estimates of the free thyroid hormone concentrations. It should however be remembered that the reference ranges provided by the manufacturers of free thyroid hormone measurement kits have been established using pools of non pregnant normal sera. Such reference ranges are no longer valid in the pregnant state because the free T4 assays are influenced by the serum changes characteristically associated with pregnancy (changes in TBG, albumin, etc.). It has therefore recently been proposed to adapt serum free T4 reference ranges to ‘laboratory-specific’ or ‘trimester- specific’ ranges for specific use during pregnancy but, so far, no consensus has been reached worldwide on such ‘pregnancy-adapted’ ranges, and it is recommended to remain cautious in the interpretation of serum free T4 levels in pregnancy (see Figure 14-4, middle panel). Each laboratory should establish its ‘normal’ reference range to correctly evaluate thyroid function tests in pregnant women 69-70. Irrespective of the techniques used to measure free T4 during pregnancy, there is a characteristic pattern of serum free T4 changes during normal pregnancy. This pattern includes a slight and temporary rise in free
  10. 10. T4 during the first trimester (due to the thyrotropic effect of hCG) and a tendency for serum free T4 values to decrease progressively during later gestational stages 71. In iodine- sufficient conditions, the physiologic free T4 decrement that is observed during the second and third trimester remains minimal (~10%), while it is enhanced (~20-25%) in iodine- deficient nutritional conditions (see Figure 14-4, lower left and right panels, respectively). Figure 4 Upper left panel: pattern of changes in serum TBG concentrations (mean + sd) in 606 normal pregnant women (from Glinoer, Ref 3). Upper right panel: pattern of changes in serum total T4 concentrations (individual results) in 98 normal pregnancies (from Kahric-Janicic, Ref 67). Middle panel: free T4 measurements in 29 women in the 9th month of gestation, using equilibrium dialysis (ED), and 9 different immunoassays (EL: Elecsys; VD: Vidas; VT: Vitros ECi; GC: Gamma-Coat; IM: Immunotech; AD: Advantage; AX: AxSYM; AC: ACS: 180; AI: AIA Pack). The boxes show the non-pregnant upper and lower reference intervals. The percentages given in the upper part of the figure show the mean decrement (in percent) of serum free T4 values compared with the mean free T4 reference value for non-pregnant subjects, provided by the manufacturer. It can be seen that free T4 values were decreased by 40% when measured by ED, and by 17-34% depending on the immunoassay employed (from Sapin, Ref 69). Lower left panel: pattern of changes in serum free T4 concentrations (individual results) in 98 normal pregnancies in the USA, with an adequate iodine intake (from Kahric-Janicic, Ref 67). Lower right panel: pattern of changes in serum free T4 concentrations (mean – sd) in 606 normal pregnant women in Brussels, with a borderline low iodine intake (from Glinoer, Ref 3).
  11. 11. Serum TSH Serum TSH values are influenced by the thyrotropic activity of elevated circulating hCG concentrations, particularly (but not only) near the end of the 1st trimester. Thus, serum TSH values decrease during the first trimester in response to hCG elevation and, in approximately one fifth of healthy pregnant women, serum TSH values may be transiently lowered to subnormal values at this time of gestation 3, 5, 6, 24, 36. By using the classical non pregnant reference range for serum TSH (0.4 mU/L for the lower limit and 4.0 mU/L for the upper limit), one might therefore misdiagnose as ‘normal’ women who already have a slight TSH elevation and, conversely, wrongly suspect hyperthyroidism in normal women who simply have a transiently blunted serum TSH. During the remainder of pregnancy, serum TSH returns progressively to the normal range. As it was the case for free thyroid hormone measurements, it has recently been proposed to use ‘trimester-specific’ reference ranges for serum TSH levels during pregnancy 72-74. Dashe et al. have recently published a “nomogram” for serum TSH changes during pregnancy 75. The authors showed that 28% of singleton pregnancies with a serum TSH greater than 2 standard deviations above the mean would not have been identified when using the nonpregnant serum TSH range. In Figure 14-5, it can be seen that the lower normal limit of serum TSH decreases to 0.03 mU/L in 1st and 2nd trimesters, and is still reduced to 0.13 mU/L in the 3rd trimester. Conversely, serum TSH levels above 2.3 mU/L (1st trimester) and 3.1-3.5 mU/L (2nd and 3rd trimesters) may already be indicative of a slight thyroid underfunction. Median and 95% TSH confidence limits (Hong Kong) Panesar et al, Ann Clin Biochem 38:329, 2001 4.5 3.5 3.5 3.5 3.5 3.1 2.5 TSH 2.3 mIU/L 1.5 1.2 1.3 1.2 0.8 1.1 0.5 0.13 0.03 0.4 0.03 0.03 0.4 1st. Trimester 2nd. Trimester 3rd. Trimester 10 20 30 40 W eeks Gestation Figure 5 Gestation-related reference intervals for serum TSH in a Chinese population (343 healthy pregnant women & 63 non-pregnant controls). The median, 2.5th and 97.5th percentiles for serum TSH values are shown in the blue boxes for each trimester. Gestation- specific reference intervals for TSH should alleviate the potential risk of misinterpretation of thyroid function tests in pregnancy (from Panesar, Ref 72).
  12. 12. Placental metabolism of thyroid hormones The placenta contains high concentrations of Type 3 or inner-ring (5) iodothyronine deiodinase 76-78. Inner-ring deiodination of T4 catalyzed by this enzyme is the source of high concentrations of reverse T3 present in amniotic fluid, and the reverse T3 levels parallel maternal serum T4 concentrations 79-82. This enzyme may function to reduce the concentrations of T3 and T4 in the fetal circulation (the latter being still contributed by 20-30 % from thyroid hormones of maternal origin at the time of parturition), although fetal tissue T3 levels can reach adult levels due to the local activity of the Type 2 deiodinase (see Chapter 15) 59. Type 3 deiodinase may also indirectly provide a source of iodide to the fetus via iodothyronine deiodination. Despite the presence of placental Type 3 deiodinase, in circumstances in which fetal T4 production is reduced or maternal free T4 markedly increased, transplacental passage occurs and fetal serum T4 levels are about one third of normal 83. Thyroxine can be detected in amniotic fluid prior to the onset of fetal thyroid function, indicating its maternal origin by transplacental transfer 84. Figure 14-6 depicts the steep maternal to fetal gradient of total T4 concentrations in early pregnancy stages. Between 6-12 weeks gestation, if maternal total T4 concentration is set to represent 100%, the total T4 concentration in the coelomic fluid would represent 0.07% and T4 in the amniotic cavity as little as 0.0003-0.0013% of maternal total T4 concentrations. Thus, the placental barrier to maternal iodothyronines is not impermeable to the transplacental passage of thyroid hormones of maternal origin, even in the 3rd trimester 59, 85. Even though very small quantitatively, such concentrations may qualitatively represent an extremely important source of thyroid hormones to ensure the adequate development of the feto-maternal unit 86, 87. Placenta : maternal Extraembryonic coelom Amniotic cavity with developing embryo : 0.05-0.2 nmol/L with coelomic fluid : 1 nMol/L serum : 150 nmol/L Figure 6 Steep gradient between maternal concentrations of thyroid hormones and those measured in the coelomic fluid and amniotic cavity with the developing embryo, during early stages of gestation.
  13. 13. Main “take home” messages Several complex physiologic changes take place during pregnancy, which tend together to modify the economy of the thyroid and have a variable impact at different time points during gestation. Human CG possesses intrinsic thyroid-stimulating activity, transiently leading to TSH suppression near the end of first trimester in ~20% of pregnancies. In 1/10th of the latter cases, serum free T4 levels may be transiently elevated above normal; in turn, these women may develop gestational transient thyrotoxicosis (‘GTT’). Hyperemesis Gravidarum (HG) is often present during the first gestational months. A significant fraction of HG women may present features suggesting hyperthyroidism, and resulting from hCG-induced thyroidal stimulation. Among the main physiologic changes in the thyroid economy during pregnancy, there is a marked increase in serum TBG and extra-thyroidal T4 distribution space, taking place in the first half of gestation. In order to maintain the homeostasis of free T4 concentrations, the thyroid machinery produces more thyroxine, until the new steady-state is reached around mid-gestation. Thereafter, changes in peripheral metabolism of thyroid hormones explain the reasons for a sustained increased production of T4, to maintain unaltered serum free T4 concentrations. Finally, caution is recommended in the interpretation of thyroid function tests during pregnancy. Patterns of the serial changes in serum total and free T4, as well as serum TSH, imply the need to better define ‘pregnancy-specific’ normative reference ranges for the most commonly used thyroid function tests during gestation. PREGNANCY AND IODINE DEFICIENCY Physiologic adaptation of the thyroidal economy associated with normal pregnancy is replaced by pathologic changes when pregnancy takes place in conditions with iodine deficiency or even only mild iodine restriction. Globally, the changes in maternal thyroid function that occur during gestation can be viewed as a mathematical fraction, with hormone requirements in the numerator and the availability of iodine in the denominator. When availability of iodine becomes deficient during gestation, at a time when thyroid hormone requirements are increased, this situation presents an additional challenge to the maternal thyroid 3, 6, 10, 88-91. Figure 14-7 illustrates the steps through which pregnancy induces a specific challenge for the thyroid gland and the profound difference between glandular adaptation in conditions with iodine sufficiency or deficiency.
  14. 14. Figure 7 From physiological adaptation to pathological alterations of the thyroidal economy during pregnancy. The scheme illustrates the sequence of events occurring for the maternal thyroid gland, emphasizing the role of iodine deficiency to stimulate the thyroidal machinery (from Glinoer, Ref 6). Thus during pregnancy, the physiologic changes that take place in maternal thyroid economy lead to an increase in thyroid hormone production of ~50% above preconception baseline hormone production. In order to achieve the necessary increment in hormone production, the iodine intake needs to be increased during early pregnancy. Iodine nutrition status before pregnancy, during pregnancy and lactation: the new recommendations In 2001, the World Health Organization officially endorsed recommendations made by international organizations such as the ICCIDD (International Council for Control of Iodine Deficiency Disorders) and UNICEF (United Nations Children’s Fund) to eliminate iodine deficiency disorders, on the basis that iodine deficiency present at critical stages during pregnancy and early childhood resulted in impaired development of the brain and consequently in impaired mental function 92, 93. Although a variety of methods exists for the correction of iodine deficiency, the most commonly accepted and applied method is universal salt iodization (USI), i.e., the addition of suitable amounts of potassium iodide (or iodate) to all salt for human and livestock consumption. In 2005, a WHO Technical Consultation has produced new guidelines for the iodine requirements and monitoring of iodine nutrition status in high risk groups such as pregnant and lactating women 1, 94-96. Before becoming pregnant, women should ideally have an average daily iodine intake of 150 µg, to ensure that their intra-thyroidal iodine stores are
  15. 15. replenished before pregnancy. Population studies carried out in the 1990s have shown that when women with an iodine intake of <100 µg/d become pregnant, the pregnancies are frequently associated with thyroid function abnormalities (mainly maternal hypothyroxinemia), resulting in excessive thyroidal stimulation and goiter formation in both the mother and offspring 4, 97-101. The general consensus reached by the WHO Technical Consultation held in 2005 was that the recommended nutrient intake (RNI) for iodine during pregnancy and breast-feeding should range between 200 and 300 µg per day, with an average of 250 µg per day. Several pregnancy population studies, carried out between 1981 and 2002, have shown that iodine supplementation maintained a normal thyroid function, thus allowing maternal hypothyroxinemia to be avoided and maternal and neonatal goitrogenesis to be prevented 11, 102-108. Recently, several studies have been published dealing with the assessment of maternal iodine intake by measurements of urinary iodine excretion (UIE). One study showed that advancing gestation time had an influence on UIE measurements in a mildly iodine-deficient pregnant population 109. In another study from Iran, the authors showed that salt iodization (national program) in the population was not sufficient to maintain median UIE values within adequate and recommended ranges throughout pregnancy, hence emphasizing the need for extra iodine supplementation means during pregnancy 110. Finally, two studies dealt specifically with urinary iodine excretion measurements in infants during the first week of life 111, 112. With regard to the upper limit of safety for the iodine intake in pregnancy, excessive levels of iodine intake may potentially cause more disease. Furthermore, certain individuals must be identified who may have side effects from excessive iodine intake, such as patients with known or underlying autoimmune thyroid disorders or autonomous thyroid tissue. Since there is no strong evidence to define clearly “how much more iodine may become too much iodine,” the most reasonable recommendation was to indicate that there is no proven further benefit in providing pregnant women with more than twice the daily RNI. Finally with regard to iodine nutrition during breast-feeding, thyroid hormone production and urinary iodine excretion return to normal, but iodine is efficiently concentrated by the mammary gland. Since breast milk provides approximately 100 µg/d of iodine to the infant, it is recommended that the breast-feeding mother should continue to take 250 µg per day of iodine (see Table 14-2). Table 2. Recommended iodine intake during pregnancy and lactation and categorization of iodine nutrition adequacy based on urinary iodine excretion Population Group Median Urinary Iodine conc. Category of Iodine intake Pregnant women 250 μg/d Lactating women 250 μg/d Pregnant women < 150 μg/L Insufficient 150 – 249 μg/L Adequate 250 – 499 μg/L More than adequate > 500 μg/L Excessive Lactating women < 100 μg/L Insufficient > 100 μg/L Adequate iodine deficiency during pregnancy.
  16. 16. Epidemiology of iodine deficiency during pregnancy Remarkable progress has been accomplished towards the control and eradication of iodine deficiency disorders following the introduction of a policy of universal salt iodization (USI) 113. A recent review of the ‘Thyromobil’ campaigns by Delange et al., that concerned several surveys of over 38,000 schoolchildren from 32 countries across four continents, showed that the progress in the control of IDD worldwide was due to the implementation of effective USI programs 114. What is the iodine nutritional situation concerning the women in childbearing age. Despite national efforts to implement the mandatory use of iodized salt, that has been in place in Switzerland – a naturally iodine-deficient country for many years –, two studies have shown that mild iodine deficiency still prevailed in pregnant women in the Bernese area 115, 116. The new tendency towards a resurgence of iodine deficiency was discovered only by constantly monitoring the iodine nutritional status in the general population, and particularly that of women in the reproductive age and during pregnancy. The findings eventually led the sanitary Swiss authorities in 1988 to further increase the iodine content of household salt above the 20 µg I/g salt content that had been in place since 1980. Another study deserves a comment. Authors have investigated changes in serum TSH near the end of pregnancies in Columbia, a country where iodized salt is used to correct IDD. In those pregnant women submitted to salt restriction during pregnancy, a significant fraction (~50%) showed a significant TSH elevation at the time of delivery, with a rapid normalization in the weeks following parturition. Such data emphasize the important public health concept that in areas where the use of iodized salt has been implemented to prevent iodine deficiency, any cause of dietary salt restriction, when it is superimposed to the iodine restriction which is common in the pregnant state, may aggravate further the risk of becoming hypothyroid. Therefore, when salt restriction is prescribed, it is highly recommended to monitor serum TSH changes and provide supplements of iodine during pregnancy 117. Another important epidemiological consideration is that the risk of iodine deprivation during pregnancy needs to be assessed locally and closely monitored over time, because mild to moderate iodine deficiency may occur in areas that are not immediately recognized as iodine-deficient. For instance, the southwestern city of Toulouse (France) was not particularly known to be iodine deficient because of its relative proximity from the sea and the fish-eating habits in the population. Nevertheless, a study performed in 1997 in a cohort of pregnant women from this area clearly showed that the urinary iodine excretion levels were too low, with over 75 % of pregnant women having excretion levels below 100 µg/L 97. Yet another epidemiological concept relates to the notion that the iodine intake may vary unexpectedly from one area to another within a given country. This occurs frequently in regions with mild to moderate iodine deficiency, because of significant variations in the ‘natural’ iodine content of food and water. A good example of this geographical variation was illustrated by a Danish study 99. In Copenhagen, pregnant women without iodine supplements had a median iodine excretion level of 62 µg/g creatinine, compared with only 33 µg/g creatinine in East Jutland. Furthermore, these striking differences were not alleviated in the pregnant women from the same two areas who received iodine supplements: 74 µg/g creatinine in Copenhagen versus 34 µg/g creatinine in East Jutland. These results indicated that iodine supplementation was insufficient and their beneficial effects did not show up in urinary excretion values, presumably because the iodine supplements were entirely taken up by the iodine-deficient – and hence stimulated – maternal thyroid glands.
  17. 17. A final general epidemiological concept is that iodine deficiency requires constant monitoring, even after the implementation of iodine supplementation in pregnant women. Since our initial studies on iodine deficiency during pregnancy in the early 90s, the majority of pregnant women receive nowadays multivitamin pills in Brussels, containing 100-125 µg iodine as a daily supplement. Despite this public health effort and improved medical awareness, a recent study of neonates in Brussels showed that their iodine nutrition status, albeit improved, had not yet normalized 118. What about the iodine nutrition status in pregnant women in the USA? The Public Health Affairs committee of the American Thyroid Association has recently reviewed the status of iodine nutritional requirements in women in the childbearing period and during pregnancy 119. The committee reviewed the different sources of dietary iodine in the population of the USA & Canada (salt, dairy products, vitamin/mineral preparations, etc.) and recommended a daily iodine intake for non-pregnant (and non-lactating) adults of 150 µg/day of iodine. The committee assessed the available information on iodine excretion levels in the USA. The successive National Health and Nutrition Examination (NHANES) surveys in the USA have clearly identified a marked decrease in urinary iodine concentrations (UIC), from a median of 321 µg/L (1971-1974) to 145 µg/L (1988-1994), with a stabilisation thereafter: 161 µg/L (2000) and 168 µg/L (2001-2002) 120, 121. Concerning the women in childbearing age and pregnant, the two most recent NHANES surveys also showed that median urinary iodine excretion levels were adequate overall: 127 and 141 µg/L, respectively (1988-94), and 132 and 173 µg/L, respectively (2001-02). However, and despite the adequacy of iodine nutrition in the general population in the USA, it is important to note that 11-12% of the general population had a UIC <50 µg/L, naturally raising a concern that iodine deficiency might still be present during pregnancy 122, 123. For women in the reproductive age (15-44 yrs), the prevalence of this target population excreting less than 50 µg of iodine/L reached 15.3% in 1988-1994 and increased slightly to 16.8% in 2001-2002. A similar trend was observed for the small number of pregnant women who were included in these surveys, with 6.9% of them excreting <50 µg/L of iodine (1988-1994) and 7.3% (2001-2002) 124. Thus, America’s diet appears to be generally iodine-sufficient, although it is highly variable from food to food, and even among foods within the same category (dairy products, for instance). There are likely to be some outliers where iodine intake may be insufficient for some people (and potentially excessive for others). One of the weaknesses of the NHANES surveys is that their design (with total anonymity) did not allow to pinpoint the geographical regions or socio-economic sections of North America where these ‘outliers’ may be more prevalent. The current data did not lead the committee to recommend iodine fortification in the diet for the population as a whole. However, for the specific case of pregnant women and women in the childbearing period, the committee did encourage manufacturers to include 150 µg of iodine in all vitamin/mineral preparations labeled for use during pregnancy and lactation. The committee also insisted on the importance of continuously monitoring the iodine nutrition status in the US population, including larger sampling of pregnant women in future surveys. The committee came to the conclusion that until additional physiologic outcome data become available, supplementation of pregnant and lactating women with 150 µg of iodine per day was in keeping with the current international recommendations and appeared safe. In a recent letter to the editor of Thyroid, Sullivan wrote that the recommendations of the committee to provide iodine supplementation during pregnancy had some inherent – and highly important – limitations 125. He noted for instance that many prenatal multivitamin pills do not include iodine and also that many pregnant women will not use supplements on a regular basis. In summary, the degree of iodine deficiency should be assessed in each concerned area specifically and the local situation correctly evaluated before embarking on medical recommendations for adequate iodine supplementation programs. Iodine deficiency
  18. 18. becomes significant during pregnancy when the iodine intake falls below 100 µg/day (see Figure 14-8). Figure 8 Schematic representation of the formation of a vicious circle during pregnancy taking place in iodine deficient conditions. Unless iodine supplementation is provided as early as possible in gestation to avoid enhanced glandular stimulation, this will, in turn, lead to goiter formation in both mother and offspring (from Glinoer, Ref 91). Metabolism of iodine during normal pregnancy After reduction to iodide, dietary iodine is rapidly absorbed from the gut. Then, iodide of dietary origin mixes rapidly with iodide resulting from the peripheral catabolism of thyroid hormones and iodothyronines by deiodination, and together they constitute the extra- thyroidal pool of inorganic iodide (PII). This pool is in a dynamic equilibrium with two main organs, the thyroid gland and the kidneys. Figure 14-9 schematically compares the kinetics of iodide in non-pregnant healthy adults with two different intake levels [a) adequate = 150 µg/day; and b) restricted = 70 µg/day] to the pregnancy situation with a comparable iodine intake of 70 µg/day. A normal adult utilizes ~80 µg of iodide to produce thyroid hormones (TH) and the system is balanced to fulfill these daily needs. When the iodine intake is adequate (150 µg/day, the average situation in the U.S., for instance) in non-pregnant conditions, a kinetic balance is achieved with a 35 % uptake of the available iodine by the thyroid (Figure 9; panel A). From the 80 µg of hormonal iodide produced each day by TH catabolism, 15 µg of iodide is lost in the feces, leaving 65 µg to be redistributed between the thyroid compartment (hence, providing 25 µg for daily TH production) and irreversible urinary losses. In such conditions, the metabolic balance is in equilibrium, with 150 µg of iodide ‘in’ & the same amount ‘out’, and 80 µg available for daily hormone production. Thus, with an iodine intake level of 150 µg/day (or above) in non-pregnant healthy adults, the system is able to maintain plentiful intra-thyroidal stores, in the order of 15-20 mg of iodine. In contrast, when the iodine intake is restricted to only 70 µg/day (a situation typical of Western Europe), the system must up-regulate the glandular iodide trapping mechanisms and increase the relative iodine intake to 50 (Figure 9; panel B). The higher uptake allows to recover 35 µg of
  19. 19. iodine from dietary intake and 33 µg from TH catabolism but, in these conditions in a non- pregnant healthy adult, this is no longer strictly sufficient to sustain requirements for the production of TH, since 80 µg of iodide is still required daily. To compensate for the missing amount (i.e. ~10-12 µg), the system must use the iodine that is stored in the gland, which therefore becomes progressively depleted to lower levels (~2-5 mg of stable iodine). Over time, if the nutritional situation remains unchanged and despite some adaptation of urinary iodine losses, the metabolic balance becomes negative. The thyroid gland tries to adapt by an increased uptake, glandular hypertrophy, and a higher setting of the pituitary thyrostat. During pregnancy, two fundamental changes take place. There is a significant increase in the renal iodide clearance (by ~1.3- to ~1.5-fold) and, concomitantly, a sustained increment in TH production requirements (by ~1.5-fold), corresponding to increased iodine requirements, from 80 to 120 µg iodide/day. Since the renal iodide clearance already increases in the first weeks of gestation and persists thereafter, this constitutes a non- avoidable urinary iodine loss, which tends to lower circulating PII levels and, in turn, induce a compensatory increase in the thyroidal clearance of iodide. These mechanisms underline the increased physiologic thyroidal activity during pregnancy. Panel C in Figure 9 indicates that when the daily iodine intake is only 70 µg during pregnancy, despite an increase in glandular uptake to 60 %, the equilibrium becomes more or less rapidly unbalanced, since the iodide entry resulting from both uptake and recycling is insufficient to fulfill the increased requirements for TH production. Calculations show that, in such conditions, ~20 µg of iodine are missing daily and, in order to sustain TH production, the glandular machinery must draw from already depleted intra- thyroidal iodine stores. Thus in about one trimester after conception, the already low intra- thyroidal iodine stores become even more depleted and, when iodine deprivation prevails during the first half, it tends to become more severe with the progression of gestation to its final stages. A second mechanism of iodine deprivation for the mother occurs later in gestation, from the passage of a part of the available iodine from maternal circulation to the fetal-placental unit. The extent of iodine passage has not yet been precisely established. At mid-gestation, the fetal thyroid gland has already started to produce TH, indispensable for the adequate development of the fetus. In summary, augmentation of iodide trapping is the fundamental mechanism by which the thyroid adapts to changes in the iodine supply, and such mechanism is the key to understanding thyroidal adaptation to iodine deficiency. During pregnancy, increased hormone requirements and iodine losses alter the preconception steady-state. When the iodine supply is restricted (or more severely deficient), pregnancy triggers a vicious circle that leads to excessive glandular stimulation 126.
  20. 20. Panel A 95 µg Intake 55 µg (150 µg) Urine Thyroid (135 µg) (35 % uptake) 40 µg 25 µg Hormone 80 µg required and (55 + 25) 80 µg Feces 80 µg provided ( 15 µg ) Panel B 35 µg Intake 35 µg (70 µg) Urine Thyroid (67 µg) (50 % uptake) 32 µg Hormone 33 µg 35 + 33 = 68 µg 80 µg Feces 12 « missing » µg (15 µg)
  21. 21. Panel C 28 µg Intake 42 µg (70 µg) Urine Thyroid (70 µg) (60 % uptake) 42 µg 62 µg Hormone 120 µg needed & only 120 µg (42 + 62) 104 µg available Feces 15-20 “missing” µg (15 µg) Figure 9 Schematic representation of the kinetics of iodide in healthy non-pregnant and pregnant adults. Panel A: non-pregnant adult with an adequate iodine intake of 150 µg/day. Panel B: non-pregnant adult with a restricted iodine intake, corresponding to 70 µg/day. Panel C: the latter condition is compared with an identically restricted level of iodine intake (i.e. 70 µg/day) in a pregnant woman. Daily TH production was set at 80 µg of iodine/day (in non-pregnant) and increased by 1.5-fold to 120 µg/day during pregnancy (from Glinoer, Ref 126). The concept of excessive thyroidal stimulation Almost two decades ago now, a novel concept was introduced. Iodine deficiency during pregnancy, even when considered to be only mild, results in prolonged enhanced thyroidal stimulation and leads to goitrogenesis in both mother and fetus 3, 4, 6. It was proposed to consider that pregnancy should be viewed as an ‘environmental’ factor to trigger the thyroid machinery and, in turn, induce thyroid pathology in areas with a marginally reduced iodine intake. In clinical practice, simple biochemical parameters have been identified to represent useful markers of enhanced thyroidal stimulation during an otherwise normal pregnancy, when iodine restriction was present. The first marker is relative hypothyroxinemia, i.e. serum free T4 concentrations that tend to cluster near (or below) the lower limit of normality. The second marker is preferential T3 secretion, reflected by an elevated total T3/T4 molar ratio. The third parameter is related to the pattern of changes in serum TSH. After the initial transient lowering phase of serum TSH due to high hCG levels in 1st trimester, serum TSH levels tend to remain stable in iodine-sufficient conditions, while they continue to progressively increase until term in iodine-deficient conditions. Serum TSH may reach levels that are twice (or even higher) the preconception serum TSH levels 101. The last parameter is related to the changes in serum thyroglobulin (TG). In mild to moderate iodine deficiency conditions, serum
  22. 22. TG increases progressively during gestation, so that at delivery, two thirds of women may have supra-normal TG concentrations. It is important to emphasize that monitoring serum TG changes during pregnancy in iodine-deficient conditions is of particular clinical value, because TG increments correlate well with gestational goitrogenesis, and hence constitute a useful prognostic marker of goiter formation, and its prevention by iodine supplementation 11. Thus, relatively simple criteria can be used to assess the regulation of thyroid function during a normal pregnancy and help defining enhanced thyroidal stimulation, based on the determinations of serum total T4 and T3, TBG, free T4, TSH, and TG levels. However, it is necessary to correctly interpret the changes occurring in each parameter as gestation progresses, with a clear understanding of the underlying mechanisms that lead to an adequate (versus a less than adequate) adjustment of the thyroidal economy to the changes associated with pregnancy, particularly in conditions with marginal iodine restriction and overt deficiency 91, 126, 127. Goiter formation in mother and progeny is the hallmark of iodine deficiency during pregnancy. Iodine deficiency is a preponderant causal factor to explain gestational goitrogenesis, affecting both mother and progeny. While goiter formation is not observed in pregnant women who reside in iodine-sufficient regions such as in the USA, several studies from Europe have shown that the thyroid volume (TV) increases significantly during pregnancy 5, 89, 91, 128. In European regions with a sufficient iodine intake, changes in TV remain minimal (10-15% on the average), consistent mainly with vascular thyroid swelling during pregnancy 100, 129. In other European regions with a lower iodine intake, observed changes were much larger, with TV increments ranging between 20-35% on the average, and many women exhibiting a doubling in thyroid size between 1st trimester and term 106, 107. In Brussels for instance before iodine supplementation was systematically prescribed, almost 10% of women developed a goiter during pregnancy, which was only partially reversible after parturition 130. Furthermore, precise measurements of TV in newborns of these mothers indicated that TVs were 40% larger in newborns from non supplemented mothers (compared with newborns from iodine-supplemented mothers), and thyroid hyperplasia already present in 10% of these infants soon after birth (compared with none in newborns from the iodine-receiving mothers) 11. Even in regions with borderline iodine sufficiency (such as in Hong Kong), recent studies have shown a high rate of maternal goiter formation, and TV changes that were correlated positively with changes in serum TG and negatively with urinary iodine concentrations 98. Studies carried out in Europe over the last decade in pregnant women with mild-moderate iodine deficiency have shown that goitrogenesis associated with pregnancy may, in fact, constitute one of the environmental factors to explain the preponderance of goiters in the female population. If true, it would be expected that an association be observed between parity and thyroid volume. Such an association has now been confirmed in a retrospective study of women from a moderately iodine-deficient region in Italy 131. The authors observed a significant association between increased thyroid volume and parity, providing the first clinical demonstration of a cumulative goitrogenic effect of successive pregnancies. Another recent study from Denmark also investigated the relationship between thyroid volume and parity 132. The authors confirmed that in Danish women aged 18-65 yrs, TVs were larger in the parous versus nulliparous women; they also showed that in this population, the differences in TV were aggravated by active smoking. Recently, two case reports showed that, in rare instances, a pre-existing goiter may present an abrupt size increase during gestation, leading to tracheal compression and respiratory symptoms. In one case, the
  23. 23. woman did not take iodine supplements and she had a low urinary iodine concentration (<50 µg/L) 133. The acute increase in goiter size was related to intrathyroidal hemorrhage that probably resulted from the thyroidal stimulation associated with the pregnant state. In the other case, there was no information on the iodine status of the woman 134. Altogether, these results confirm the notion that several environmental factors may play a role in explaining goiter formation, tending to reinforce each other: iodine deficiency as the background, successive pregnancies as the triggering factors, and smoking habits as an additional reinforcement causal agent. In summary, pregnancy is a strong goitrogenic stimulus for both the mother and fetus, even in areas with only a moderate iodine restriction or deficiency. Maternal goiter formation can be directly correlated with the degree of prolonged glandular stimulation that takes place during gestation. Goiters formed during gestation only partially regress after parturition, and pregnancy therefore constitutes one of the environmental factors that may help explain the higher prevalence of goiter and thyroid disorders in women, compared with men. Most importantly, goiter formation also takes place in the progeny, emphasizing the exquisite sensitivity of the fetal thyroid to the consequences of maternal iodine deprivation, and also indicating that the process of goiter formation already starts during the earliest stages of the development of the fetal thyroid gland. Monitoring the adequacy of iodine intake and implementing iodine nutrition fortification during pregnancy The best single parameter to evaluate the adequacy of iodine nutrition in a population is provided by measurements of the urinary iodine excretion (UIE) levels in a representative sample of the population. Although UIE is highly useful for public health estimations of iodine intake in populations, UIE alone is not a valid diagnostic criterion in individuals. To assess the adequacy (i.e. the long term sufficiency) of iodine nutrition in an individual, the best single parameter would be to estimate the amount of iodine stored within the thyroid gland, corresponding to ~10-20 mg of stable iodine. This parameter is, however, not measurable in practice. Therefore in a given pregnant woman, the best surrogate is to evaluate those thyroid parameters that have been shown to be sensitively altered when pregnancy takes place in iodine-deficient nutritional conditions: a lowering in serum free T4, a rise in serum TSH, a progressive increase in serum TG, an elevation of total molar T3/T4 ratio, and finally an increase in TV. Concerning the implementation of iodine fortification during pregnancy, different epidemiologic situations must be distinguished. In countries with a longstanding and well- established USI program, pregnant women are not at risk of having iodine deficiency. Therefore, no systematic dietary fortification needs to be organized in the population. It should, however, be recommended individually to women to use vitamin/mineral tablets specifically prepared for pregnancy requirements and containing iodine supplements. In countries without an efficient USI program, or with an established USI program where the coverage is known to be only recent or partial, complementary approaches are required to reach the RNI for iodine. Such approaches include the use of iodine supplements in the form of potassium iodide (100-200 µg/day) or the inclusion of KI (125-150 µg/day) in vitamin/mineral preparations manufactured for pregnancy requirements. Finally in those areas with severe iodine deficiency and, in general, no accessible USI program and difficult socioeconomic conditions, it is recommended to administer iodized oil orally as early during gestation as possible.
  24. 24. Prevention of pregnancy-related goitrogenesis To prevent gestational goitrogenesis, women should ideally be provided with an adequate level of iodine intake (~150 µg/day) already long before conception. Only then can a long term steady-state be achieved with sufficient intra-thyroidal iodine stores (10-20 mg), thus avoiding triggering of the thyroid machinery that occurs once gestation begins. To achieve such goal, public health authorities ought to implement dietary iodine supplementation national programs in the population. Correcting this public health problem has been the aim of a massive global campaign that was undertaken 10-15 years ago worldwide, based on universal salt iodization (USI), and that has shown remarkable progress so far 96, 122, 123, 135. Until 1992, most European countries used to be moderately or more severely iodine deficient. A survey carried out in 12 European countries (using a mobile unit, the ‘ThyroMobil’ van) has indicated that children’s iodine nutrition status had markedly improved in many - albeit not in all - countries surveyed 136. As an example, the ‘ThyroMobil’ survey in Belgian children has indicated that the iodine nutritional status had improved – only slightly – in recent years, with a median urinary iodine excretion level of 80 µg/L (compared with 55 µg/L earlier) and a goiter prevalence of 6% (compared with 11% earlier) in a cohort of representative 6-12 year-old schoolchildren 137. These as well as other available data demonstrate that silent iodine prophylaxis is not sufficient to restore an adequate iodine balance, and that more stringent prophylactic measures need to be taken by public health authorities. How much supplemental iodine should be given to prevent goiter formation remains a matter of local appreciation and depends primarily on the extent of pre-existing iodine deprivation 102. Since the ultimate goal is to restore and maintain a balanced iodine status in expecting mothers, this can be achieved in most instances with supplements of 100-200 µg of iodine per day given during pregnancy (see Figure 14-10). In practice, this requires the administration of multivitamin pills designed specifically for pregnancy purposes and containing iodine supplements. It should be remembered that, because of the longstanding restriction in dietary iodine before the onset of a pregnancy, a lag period of approximately one trimester is inevitable before the benefits of iodine supplementation to improve thyroid function can be observed 11, 89. Because of salt restriction, the use of iodinated salt is obviously not the ideal vector to supplement mothers during gestation 138. Finally, caution is needed to avoid iodine excess to the fetal thyroid. The fetal thyroid gland is exquisitely sensitive to the inhibitory effects of high iodine concentrations, and a recent study showed that inhibitory effects of high iodine loads could lead to opposite variations in maternal and neonatal thyroid function, i.e. with facilitation of thyroid function in the mother but aggravation in the neonate 105.
  25. 25. Iodine & Thyroid Volume in Pregnancy 50 P < 0.001 Increment in T. V. (in %) 40 P < 0.05 30 30% 20 10 15% 8% 0 Placebo KI KI+LT4 N=60 N=60 N=60 Goitrogenesis in 75 % 34 % 25 % Figure 10: Randomized clinical trial with placebo versus KI (100 µg iodine/day) or KI + l-T4 (100 µg iodine/day and 100 µg T4/day) given during pregnancy in women with moderate iodine deficiency and laboratory features of thyroidal stimulation. In the placebo-treated group, TV increased by a mean 30% and goiter formation occurred in 75% of the women. In both actively-treated groups, the increments in TV were significantly reduced (to only 15% and 8%), as was goiter formation (from Glinoer, Ref 11). The case of pregnancy in severe iodine deficiency Because of the difficulties inherent to field studies in most areas with severe iodine deficiency, there have been no systematic studies to carefully assess pregnancy-related changes in goiter size. Until a decade ago, it was practically not feasible to obtain echographic measurements of the thyroid gland on a large and representative scale; it was even more difficult to sequentially observe goitrogenic changes associated with gestation. This situation is presently rapidly evolving, due to the possibility to adapt and use the ThyroMobil technology to field studies in remote areas in Eastern Europe, Africa, and Asia, and the introduction of universal salt iodization programs 139. In areas with severe iodine deficiency, iodine supplements have been administered to pregnant women using iodized salt, potassium iodide drops and iodized oil (given intramuscularly or orally), as emergency prophylactic and therapeutic approaches to avoid endemic cretinism. Several such programs have conclusively demonstrated their remarkable efficiency to prevent and treat endemic goiter, as well as to eradicate endemic cretinism 140. The results of such studies have indicated that pregnant women who reside in severely iodine-deficient regions can adequately be managed with iodine supplementation. However, except for emergency situations, there is presumably no need to use supra-physiologic amounts of iodine to normalize thyroid function parameters. Although it has not been
  26. 26. possible, thus far, in the setting of difficult field studies to evaluate quantitatively the reduction in goiter size or goiter prevalence associated with the clear improvement in thyroid function, goiter reduction is undoubtedly a side benefit of the overall improvement in the iodine nutritional status 108, 141-144. Recommendations and ‘take home’ messages. Iodine deficiency (ID) during pregnancy occurs when gestation takes place in areas with even only a mild iodine restriction. Since this occurs at a time when thyroid hormone requirements are increased, ID induces a vicious circle leading to enhanced thyroidal stimulation, relative hypothyroxinemia and gestational goitrogenesis, affecting both mother and fetus. Women in the childbearing period should have an average daily iodine intake of 150 µg. During pregnancy and breastfeeding, the recommended nutrient intake (RNI) for iodine ought to be increased to 200-300 µg per day (250 µg/day on the average). To avoid risks potentially associated with iodine excess, the iodine intake of pregnant women and breastfeeding mothers should not exceed twice the daily RNI for iodine (i.e. <500 µg iodine/day). To assess the adequacy of iodine intake during pregnancy at the population level, urinary iodine excretion (UIE) should be measured in a representative sample of the population: ideally, UIE should range between 150-250 µg/L. Measuring UIE is not a valid tool to assess the adequacy of iodine nutrition at the level of individuals. For this purpose, only the pattern of changes in thyroid function parameters can provide the required evaluation. In order to reach the daily RNI, multiple means must be considered, tailored to the characteristics of iodine intake levels in a given population. Different situations must be distinguished: In countries with iodine sufficiency or well-established universal salt iodization (USI) programs, pregnancies are not at risk of having iodine deficiency. No systematic dietary fortification needs to be organized in the population, but women can individually be recommended to use multivitamin tablets containing iodine supplements during pregnancy. In countries without USI program or established USI programs where the coverage is known to be only partial, iodine supplements should be given to all pregnant women, in the form of KI (100-200 µg/day) or iodine-containing multivitamin pills especially designed for pregnancy purposes. Finally, in remote areas with no accessible USI programs, difficult socio-economic conditions, and frequently with severe iodine deficiency, prophylactic & therapeutic iodine fortification of pregnant women becomes an emergency to avoid endemic cretinism. It is recommended to administer iodized oil orally (400 mg of iodine) once, as early as possible during gestation.
  27. 27. AUTOIMMUNE THYROID DISEASE AND PREGNANCY Effects of pregnancy on immune function Many autoimmune diseases are affected by pregnancy. In a normal pregnancy, the maternal immune system undergoes a major adjustment to allow the maintenance of what may be immunologically considered a foreign body - with 50% paternal genes -, the developing fetus. Alterations in maternal immune system which permit the successful implantation of the fetal allograft have not yet been definitively identified, but the factors leading to this immune tolerance seem likely to be partially responsible for the generalized improvement in autoimmune thyroid diseases, characteristic of the pregnant state. In normal pregnancy, along with the overall dampening of the immune system, maternal immune responses have been shown to shift, moving immune responses away from Th1 cell-mediated immunity and reducing antibody production, hence leading to a pattern were both arms of immune responses are reduced 145. Table 14-3 summarizes the main effects of pregnancy on lymphocyte subsets in patients with and without thyroid autoantibodies 146-149. Precise mechanisms by which thyroid antibodies, as well as those directed against other tissues, are suppressed during pregnancy, and often exacerbate after delivery, remain relatively obscure. Presumably, the rapid reduction in immune suppressor functions following delivery leads to the reestablishment and exacerbation of these conditions. The postpartum exacerbation of autoimmune thyroid disease is one of the most striking examples of this phenomenon. This pattern is especially well illustrated in patients with Hashimoto's disease, in euthyroid patients with positive thyroid antibodies who develop postpartum thyroid dysfunction, and in Graves' disease patients who frequently present exacerbations and recurrences of thyrotoxicosis after parturition 150-160. Table 14-3. Effects of Pregnancy on Lymphocyte Subsets in Patients with and Without Thyroid Autoantibodies. Decreased CD4+ and increased CD8+ T cells in all patients. Increase in CD29+/CD45RA+ ratio (supressor-inducer T cell function) during postpartum in all patients. Decrease in TPO-Ab and TG-Ab during pregnancy and a marked increase during postpartum. In patients who develop postpartum thyroid disease: a) thyroid antibodies are higher during and after pregnancy. b) there is an increased prevalence of HLA DR3+ antigens. Thyroid autoimmunity and disorders of female reproduction Infertility Infertility is defined as the absolute inability to conceive after one year of regular intercourse without contraception. The overall prevalence of infertility is estimated to range from 10% to 15% and has remained stable over the past few decades. The work up of infertile women usually identifies different causal factors, including male-factor infertility in 30%, female causes of infertility in 35%, a combination of both male and female infertility in 20%, and idiopathic infertility in 15%. Female causes of infertility comprise endometriosis, tubal occlusion and ovulation dysfunction. Among the factors that may negatively influence normal fertility, immunologic factors are known to play an important role in the reproduction processes of fertilization, implantation and early development of the embryo. Different investigations support the association between reproductive failure and abnormal
  28. 28. immunological test results, including anti-phospholipid, anti-nuclear antibodies and organ specific autoimmunity, among which the presence of antithyroid antibodies 161, 162. With regard to thyroid dysfunction, clinical hypothyroidism is clearly associated with female infertility and, in women in the reproductive age, autoimmune thyroid disease (AITD) is the most common cause of hypothyroidism. The association between subclinical hypothyroidism (SCH) and infertility has been evaluated in different studies, but most of the latter are retrospective and uncontrolled 163. The impact of AITD on infertility in women without thyroid dysfunction is even much less clear and the clinical relevance of such possible association remains controversial. In a series of recent studies by the group of Poppe in Brussels, new light was shed on these difficult issues. They performed a controlled prospective study of 438 consecutive couples consulting for infertility and showed that female infertility was significantly associated with AITD without thyroid dysfunction (the strongest association was found in women with endometriosis). In a follow-up study of infertile couples who benefited from Assisted Reproductive Techniques (ART), these authors showed that medically- assisted conception and onset of gestation were not hampered by AITD, but a successful outcome of the ongoing pregnancies was significantly reduced in those women with AITD due to greater early pregnancy loss (see Figure 14-11) 164-167. The main practical question is whether one should give the benefit of thyroxine administration to infertile women who have positive thyroid antibodies with variable degrees of thyroid insufficiency. Obviously, overt thyroid dysfunction should be treated before conception or planned ART. Since SCH has a negative impact on the outcome of pregnancy after ART, thyroxine treatment should also be advised. Evidence on the treatment of isolated autoimmune features, but without thyroid dysfunction, was insufficiently documented until recently to advise prompt action (see later section on medical interventions). LB n=8 Pregnant 47% n=17 55% Ab + MC n=31 n=9 15% NP 53% n=14 45% IVF LB n=203 n=52 Pregnant 74% n=70 Ab - 41% n=172 MC 85% n=18 NP 26% n=102 Ab = TPO-antibodies 59% NP = No Pregnancy LB = Life Born MC = Miscarriage Figure 11: Outcome of Assisted Reproduction (IVF) in 203 women with (15%) and without (85%) thyroid autoimmunity (TAI). The rate of successfully-induced pregnancies was not decreased in TAI positive women (~50%), but miscarriages occurred twice more frequently in them (53 versus 26%; O.R for miscarriage in TAI positive cases = 3.77) (from Poppe, Ref 165).
  29. 29. Another interesting development concerns reproductive function in males with thyroid dysfunction. In males, hyperthyroidism causes alterations in spermatogenesis and fertility, and most studies show that hyperthyroid male patients have abnormalities in seminal parameters, mainly sperm motility. These abnormalities tend to improve and normalize when euthyroidism is restored by treatment. Concerning hypothyroidism in males, severe and prolonged thyroid insufficiency may impair reproductive function, particularly when its onset occurs in childhood. Severe juvenile hypothyroidism may also be associated with precocious puberty. Finally, patho-zoospermia and astheno-zoospermia seem more prevalent in infertile males who present features of AITD 168-170. An interesting study was recently published by Krassas et al. 171. Among 71 men with thyroid dysfunction (1/3rd with hyperthyroidism and 2/3rd with hypothyroidism), the authors found an elevated frequency of erectile dysfunction (56/71; 79%). Moreover, the restoration of a euthyroid status by thyroid treatment also restored a normal (or significantly improved) erectile function. Miscarriage Thirty-one percent of all pregnancies end in miscarriage. Generally, women who experience a single pregnancy loss do not routinely undergo an evaluation for the cause of miscarriage. Women who experience recurrent miscarriages (i.e. 0.3%-5% of women), which is defined as three or more spontaneous miscarriages without an intervening live birth, should thoroughly be evaluated for an underlying etiology (such as infections, auto-immune disorders, exposure to drugs, etc.) 172-174. An association between AITD and miscarriage was first reported in 1990-91, as a serendipitous discovery 175, 176. Since then, an impressive number of studies have confirmed that women with AITD, without overt thyroid dysfunction, have a significantly increased risk of miscarriage. Furthermore, this risk was shown to be independent of the presence of antinuclear and anticariolipin antibodies and, in most studies, increasing age appeared as an independent risk factor for a miscarriage. In Table 14-4, the information available from thirteen studies investigating the risk of a miscarriage in relation with the presence (versus the absence) of AITD has been compiled 177. The authors concluded that the overall risk of having a miscarriage was 3-fold to 5-fold greater in women with AITD (and apparent euthyroidism). In another review by Stagnaro- Green & Glinoer in 2004, a classification was attempted by examining separately an association between AITD & miscarriage (in 5 studies), between AITD & recurrent miscarriage (in 7 studies), and finally between AITD & early pregnancy loss after ART (in 5 studies) 178. Overall and with only few exceptions, all studies documented a statistically significant relationship between thyroid autoimmunity and an increased risk of pregnancy loss. Finally in 2004, Prummel & Wiersinga published a meta-analysis of both the case- controlled and longitudinal studies published since 1990, after the association between miscarriage and AITD was first described 179. The results of this meta-analysis amply confirmed that an association exists, with an overall increased relative risk of a miscarriage of 2.73 in women with AITD. Table 14-4 Miscarriages in women with positive thyroid antibodies First Year Country Number Positive Miscarriage P Characteristics author of thyroid rate in value of selection subjects antibodies of the study Ab Ab groups pos. neg. (or control women)
  30. 30. Stagnaro- 1990 U. S. A. 552 19.6 % 17.0 8.4 % = unselected Green % 0.011 population vs study Glinoer 1991 Belgium 726 6.2 % 13.3 3.3 % < unselected % 0.005 population vs study Lejeune 1993 Belgium 363 6.3 % 22.0 5.0 % < unselected % 0.005 population, vs before 14 wks gestation Pratt 1993 U. S. A. 42 31.0 % 67.0 33.0 % n.a. recurrent % spontaneous vs abortions Singh 1995 U. S. A. 487 22.0 % 32.0 16.0 % = pregnant with % 0.002 assisted vs reproductive techniques Bussen 1995 Germany 66 17.0 % 36.0 7.0 % < 0.03 recurrent % spontaneous vs abortions Iijima 1997 Japan 1179 10.6 % 10.4 5.5 % 0.05 unselected % < population vs study Esplin 1998 U. S. A. 149 33.0 % 29.0 37.0 % 0.05 recurrent % > pregnancy loss vs Kutteh 1999 U. S. A. 900 20.8 % 22.5 14.5 % = 0.01 two or more % consecutive vs abortions Muller 1999 Netherlands 173 14.0 % 33.0 19.0 % = 0.29 pregnant with % assisted vs reproductive techniques Bussen 2000 Germany 48 30.6 % 54.2 8.3 % = failure to % 0.002 conceive after 3 vs cycles of IVF Dendrinos 2000 Greece 45 32.5 % 37.0 13.0 % < 0.05 recurrent % spontaneous vs abortions Bagis 2001 Turkey 876 12.3 % 50.0 14.1 % < unselected % 0.0001 population vs study Foot-note to Table 14-4: summary of information provided by the analysis of 13 studies carried out over the last decade in three continents. Over 5,500 women were investigated,
  31. 31. both as study cases and controls. Prevalence of AITD varied widely, from 6% in Brussels to 33% in Salt Lake City. Together, the main results (except in 2 studies) concurred to establish that AITD is significantly associated with an increased miscarriage rate. To find an association between AITD and miscarriages does not imply a causal relationship, as underlying causal mechanisms might also be attributable to a combination of factors that would potentially lead to miscarriage by themselves. Three main hypotheses have been proposed. The first is that miscarriage is linked to a generalized immune imbalance. For instance, women who have had multiple miscarriages have an increased number of CD5/20+ B cells compared with women who have had one or none. Moreover, abnormal T- lymphocyte function has been reported in women with AITD, including a higher number of endometrial T cells. Finally, aberrant immune recognition of thyroglobulin (Tg) and placental antigens by antibodies to Tg has been demonstrated in mice immunized with human Tg, and resulted in decreased fetal and placental weights 180-182. Thus, based on this 1st hypothesis, AITD would merely represent a marker of an underlying, more generalized immune imbalance that, in turn, would explain a greater rejection rate of a fetal graft. In the second hypothesis, the presence of AITD is thought to be associated with inappropriate low levels of thyroid hormones for the given gestational period, despite apparent biological euthyroidism. Although this hypothesis has sometimes been undermined by the difficulty in defining strictly normal thyroid function tests during pregnancy, data to support it have been obtained from women at high risk of miscarriage, among whom thyroid hormone levels were significantly reduced only in those who subsequently actually miscarried. For instance in the study by Bagis et al., only women with AITD and who experienced a miscarriage showed a difference in median serum levels of TSH and T4 compared to women without AITD 183. Thus, based on this 2nd hypothesis, AITD would be associated with a subtle deficiency in thyroid function, i.e. a lesser ability to adapt adequately to the changes associated with the pregnant state, because of a reduced functional reserve characteristic of chronic thyroiditis. The third hypothesis is based on maternal age. Women with AITD are generally older than healthy controls and increased age is an independent risk factor for miscarriage. Thus, based on this 3rd hypothesis, AITD could act by delaying the occurrence of conception because of its known association with infertility. Thyroid antibody-positive women would tend to become pregnant only at an older age (3-4 years older, on the average) and be more prone to pregnancy loss. Overall, these hypotheses do not contradict one another, and it remains plausible that the increased risk of pregnancy loss associated with AITD results from a combination of several independently harmful factors 184-189. For more detailed insight into this complex topic, the readers are referred to the recent review by Poppe et al 190. Women undergoing ART Several studies have examined whether miscarriages were more frequent in infertile women who underwent ART, according to the presence versus absence of thyroid autoimmunity. While some studies showed a 2-fold to 3-fold difference in the miscarriage rate in thyroid antibody-positive versus antibody-negative patients, other studies did not confirm such findings 165, 184, 191-194. The largest of these series (retrospective) failed to demonstrate an adverse effect on the miscarriage rate in antibody-positive versus antibody-negative women undergoing ART 194. The prevalence of thyroid autoimmunity, in women undergoing ART, was examined in four studies and found to range between 14%-22%, a prevalence that was not statistically different from the prevalence of thyroid antibody in women who did not undergo ART 165, 192, 193, 195. Pregnancy rates have also been examined in women with or without thyroid autoimmunity undergoing ART and the results were also conflicting. In three of these studies, there was no difference in the overall pregnancy rate (see also Figure 14-11) 165, 184, 196. In other studies, however, pregnancy rates were found to be lower by 1.5-fold to 2-fold in thyroid antibody-positive women, compared with those without antibodies 191, 197. In summary, the literature on pregnancy loss related to women with thyroid