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  • 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. 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. 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. 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. ‘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. 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. ~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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
  • 32. autoimmunity undergoing ART is mixed. The methods of ART were not consistent between the series nor were the causes of infertility controlled for among the various studies. Given that the majority of the studies did find a relationship, there is at least a suggestion that such a relationship may exist, but without sufficiently clear evidence to draw a definitive conclusion. Medical intervention in women with AITD Medical intervention to reduce the miscarriage risk in women with AITD consists of immunomodulation or thyroxine administration. Successful modulation of the immune system was reported in patients with AITD who received immunoglobulins with (or without) additional heparin or aspirin 198-200. Although these treatments were beneficial in terms of pregnancy outcome, the studies included only a small number of patients, as well as women with auto- antibodies other than thyroid antibodies, and often lacked appropriate controls. In the study by Vaquero et al, a comparison was made between the beneficial effects of immunoglobulins and thyroid hormone extracts (started before conception and continued until mid-gestation) on the outcome of pregnancy in women with AITD with a history of recurrent miscarriage 201. In the 16 women treated with thyroid hormones, significant improvement was observed in the live birth rate compared with that among the 11 women who received immunoglobulins (81% versus 51%). Criticisms of the study related to the small number of patients and the fact that thyroid hormone extract therapy was started before conception 188. Negro et al. performed two studies, one in women who became pregnant after use of ART and the second in spontaneously pregnant women 192, 202. In the first study, the miscarriage rate was reduced to 33% among thyroxine-treated women, compared with 52% among untreated controls, although this difference was not significant, probably because of the small number of patients. In the second study, the same group of authors followed up a large group of pregnant women, 12% of whom were positive for AITD. Half of the AITD-positive women were treated with thyroxine during gestation, while the other half was left untreated. The end points of the study were outcomes of pregnancy and changes in thyroid function, assessed by comparing the women with AITD with and without treatment and also the healthy pregnant controls. Striking reductions in the rates of miscarriage (by 75%) and premature delivery (by 69%) were reported among women with AITD who had received thyroxine since early gestation and throughout pregnancy. Furthermore, thyroxine-treated women with AIT maintained a euthyroid status, while free T4 decreased by 30% and TSH levels increased progressively during gestation in the untreated group; 19% of the latter women became subclinically hypothyroid at the time of parturition. The study was criticized because it was not placebo-controlled or double-blinded. It did, however, provide prospective data from the first randomized trial that confirmed the efficacy of thyroxine administration in pregnant, euthyroid women with autoimmune features 203. These findings have implications for screening and medical intervention. For instance, if delayed conception plays a significant role to explain decreased fertility in women with AITD, it would certainly constitute an argument for screening systematically infertile women for the presence of mild thyroid underfunction that is so frequently associated with thyroid antibodies, particularly when women seek medical advice before IVF procedures. Such an approach was used in Finland in 2000 204. A study by Arojoki et al. showed a high prevalence of women with elevated serum TSH levels, an association between oligo- amenorrhea and abnormally elevated serum TSH values and an overall improvement in the success rate of induced pregnancies after thyroxine administration. Finally, women with AITD could be advised to plan for a pregnancy at a younger age, although this type of medical advice is more easily said than applicable in practice. To conclude on this section, although a clear association exists between thyroid autoimmunity and pregnancy loss, systematic screening can not be universally
  • 33. recommended at present time, at least until adequately designed therapeutic trials will demonstrate beyond doubt a clear reduction in the rate of miscarriage with thyroxine treatment. This being said, more and more data point to the growing interest of screening as well as early thyroxine administration before/during pregnancy, and many centers, in Europe and elsewhere, already routinely screen women with infertility and/or miscarriage for the presence of thyroid autoimmunity and dysfunction. Effects of pregnancy on thyroid function in women with thyroid auto-antibodies Table 14-5 lists the various types of autoimmune thyroid disorders that can be found in the pregnant and postpartum population. These aspects are also discussed in greater detail below and postpartum thyroiditis is reviewed in Chapters 8 and 13. Table 14-5. Autoimmune Thyroid Disease During Pregnancy and the Postpartum Period 1. Primary hypothyroidism a) Thyroid destruction (Hashimoto's disease) b) Circulating TSH-receptor-blocking antibody 2. Asymptomatic (euthyroid) autoimmune disease a) Increased risk of developing subclinical hypothyroidism during pregnancy b) Increased risk of spontaneous miscarriage 3. Postpartum thyroid disease (PPTD) a) Hyperthyroidism b) Hypothyroidism c) Combinations 4. Graves' Disease a) Pre-existing b) Gestational exacerbation and remission c) Postpartum exacerbation The prevalence of AITD in the pregnant population is comparable to that found in the general female population with a similar age range, i.e. between 5-15% 205. In first trimester patients with gestational diabetes mellitus, the prevalence of thyroid antibodies is even higher (20-25%) 206, 207. Taken together, the high frequency of thyroid antibodies, increased risks of miscarriage, risks of developing hypothyroidism with the progression of gestation, and finally the observation that postpartum thyroiditis occurs in one half of women with AITD led us to recommend that all pregnant patients be screened for the presence of TPO antibodies during the 1st trimester of pregnancy 208. More than a decade ago, we undertook a prospective study in women with AITD and a normal thyroid function in early pregnancy. The aim was to evaluate sequentially the changes in thyroid function occurring with progression of gestation to term, without medical intervention 209. The study showed that despite the expected decrease in antibody titers during gestation, thyroid function gradually deteriorated towards hypothyroidism in a significant fraction of such women (see Figure 14-12). In the 1st trimester, serum TSH (albeit within the normal range) was already significantly shifted to higher values in women with AITD, compared with normal pregnant controls. Serum TSH remained higher throughout gestation and at parturition 40% of AITD-positive women had a serum TSH >3 mU/L, with almost one-half of them above 4 mU/L. Thus, while women with AITD were able to maintain a normal thyroid function in early gestation (due to sustained thyrotropic stimulation), their mean serum free T4 levels were significantly reduced to (or below) the lower limit of the normal reference range at delivery. Average reduction in serum free T4 reached 30% and almost one half of these women had free T4 values in the hypothyroid range by the time of delivery, confirming that these women have a reduced functional thyroid reserve. The risk of progression to hypothyroidism could be predicted from serum TSH levels and TPO-Ab titers measured in early pregnancy. When serum TSH was already above 2.5 mU/L and/or TPO- Ab titers above 1,250 U/mL before 20 weeks, these markers were indicative of the propensity to develop hypothyroidism by the end of pregnancy. These observations are important, providing clinicians with simple tools to identify during early gestation those
  • 34. women who carry the highest risk. As a consequence, thyroid function can then be closely monitored and preventive thyroxine treatment administered, to avoid the potential deleterious effects of hypothyroxinemia on both maternal and fetal outcomes. Figure 12a: Changes in TPO-Ab in pregnant women with AITD. There was a marked reduction in antibody titers, by 50-60% on the average (solid lines represent asymptomatic euthyroid women; dotted lines women with known hypothyroidism) (from Glinoer, Ref 209).
  • 35. Figure 12b: Among women with thyroid antibodies, a progressively increasing fraction developed biochemical hypothyroidism, with 10% of them having a basal serum TSH >3 mU/ L in 1st trimester, 20% in 2nd & 3rd trimesters, and finally ~40% at delivery (from Glinoer, Ref 209). TPO-Ab - TPO-Ab + Figure 12c : Mean serum free T4 concentrations at delivery in women with and without thyroid immunity. In women with AITD, mean serum free T4 was not only significantly lower than in controls, but in addition, was at the lower limit of normality (from Glinoer, Ref 209).
  • 36. Recommendations and main ‘take home’ messages Pregnancy dampens the immune system, leading to a pattern where both arms of the immune responses (cell-mediated and humoral) are reduced. The rapid reduction in immune suppressor functions following delivery leads to the re-establishment and exacerbation of these conditions during the postpartum. Even in the absence of evident thyroid dysfunction, there is good evidence to suggest that thyroid autoimmunity is associated with an increased risk of infertility. This constitutes an argument for the systematic screening of infertile women for the presence of mild thyroid underfunction, frequently associated with thyroid autoimmunity, particularly when these patients seek medical advice before in vitro fertilization procedures. With regard to pregnancy loss, the vast majority of available studies have clearly established that thyroid autoimmunity is associated with a significant increase in the risk of miscarriage. Association does not imply causality and the etiology of this association is probably multi- factorial, including underlying dysregulation of the immune system, subtle forms of mild thyroid failure, and older age. Although there is a positive association between presence of thyroid antibodies & pregnancy loss, universal screening for thyroid antibodies (and possible treatment) can not be recommended at this time. With regard to the repercussions of positive thyroid antibodies, the main risk is the occurrence of maternal hypothyroidism, with its potential deleterious effects for both the mother and fetus. This could be prevented by systematic screening for thyroid dysfunction and presence of thyroid antibodies during early gestation, followed by the administration of thyroxine treatment when required.
  • 37. PRIMARY HYPOTHYROIDISM Clinical epidemiology and causal factors The prevalence of hypothyroidism during pregnancy in Western countries is estimated to be 0.3-0.5% for overt hypothyroidism (OH) and 2-3% for subclinical hypothyroidism (SCH) 208-211. On a worldwide basis, the most important cause of maternal thyroid deficiency remains iodine deficiency, which is known to affect over 1.2 billion individuals 139. Thyroid antibodies are found in 5-15% of normal women in the childbearing age and, when the iodine nutrition status is adequate, the main cause of hypothyroidism during pregnancy is chronic autoimmune thyroiditis. Data on the prevalence of thyroid autoimmune features in pregnant women with a diagnosis of hypothyroidism have recently been reviewed by Glinoer 212. Ten studies were analyzed, of which 6 were retrospective (see Table 14-6). The overall prevalence of hypothyroidism was 2.2% to 3.4%, depending on study design. Some of these studies encompassed women already known to be hypothyroid, while in other studies the diagnosis was based on screening by serum TSH measurements, which was usually carried out before 20 weeks of gestation. It is also important to note that the cut-off level for an abnormal serum TSH differed among studies (from >3 mU/L to >6 mU/L). Interestingly, in a recent study by Casey et al. where the lowest serum TSH cut-off limit was employed, the highest prevalence of gestational hypothyroidism was observed 213. Another variable was the timing of serum TSH determinations, which varied from 5 to 20 weeks of gestation, a factor that may also have impacted on final prevalence figures. Altogether, the analysis of the data showed that thyroid antibodies were resent in 25% to 77% of hypothyroid pregnant women, with a mean prevalence of 46%. In those studies where epidemiologic information was available on groups of control women, the data showed that thyroid autoimmunity was 5.2-fold more frequent in women with a diagnosis of hypothyroidism, compared with euthyroid controls (mean of 48.5% versus 9.2%). It is important to emphasize that the prevalence of thyroid antibodies in pregnant hypothyroid women depends on the severity of thyroid dysfunction. For instance in the study by Allan et al., the prevalence of thyroid antibodies reached 55% among the women with a modest elevation in serum TSH (6-10 mU/L), while it exceeded 80% among the women with a markedly elevated serum TSH (10-200 mU/L) 211. Thus, evidence from literature amply confirms that chronic autoimmune thyroiditis represents the main cause of gestational hypothyroidism. Other causes, though much less frequent, include the previous radical treatment of hyperthyroidism using radioiodine ablation or surgery, as well as surgery for thyroid tumors. A special mention should be made of recent studies showing that in pregnant women with diabetes mellitus type 1, thyroid dysfunction, mainly subclinical hypothyroidism, may even be more prevalent (27%-45%) 214, 215. A hypothalamic-hypophyseal origin of hypothyroidism is rare, and can include lymphocytic hypophysitis occurring during pregnancy or postpartum 216. Other rare causes to consider in the differential diagnosis of hypothyroidism are those associated with the presence of TSH receptor ‘blocking’ antibodies. In such patients, hypothyroidism is presumably caused by interference in TSH to TSH-receptor interactions. Even though extremely uncommon, the clinical significance of this problem in the pregnant state is that blocking antibodies may be transferred to the fetus and thus cause intrauterine or transient neonatal hypothyroidism 156, 217-221. Table 14-6: Thyroid Autoimmunity in Pregnant Women with a Diagnosis of Hypothyroidism
  • 38. Type of Country Hypothyroid Timing of Prevalence First Author Study pregnant screening of thyroid (Year) women (N) (weeks) antibodies (Reference N°) R USA 49/2.000 15-18 58 % Klein (2.5%) (TPO-Ab) (1991) (TSH: > 6 mU/ (versus 11% (210) L) in C) R USA 68 Before 37% Leung (1981-90) (TSH: > 5 mU/ pregnancy (MIC-Ab) (1993) L) and/or at 1st (222) prenatal visit P Belgium 41/1.900 First 40% Glinoer (1990-92) (2.2%) prenatal (TG-Ab and/ (1995) (TSH: > 4 mU/ visit or TPO-Ab) (32) L) (versus 6.4% in C) P Japan 102 12 66% Fukushi (1986-98) (TSH: >?) (TG-Ab and/ (1999) (not specified) or TPO-Ab) (223) R USA 62 Before or 77% Haddow (1987-90) (TSH: > 5 mU/ during (TPOAb) (1999) L) pregnancy (versus 14% (224) in C) R USA 209/9.403 15-18 60% Allan (1990-92) (2.2%) (TG-Ab and/ (2000) (TSH: > 6 mU/ or TPO-Ab) (211) L) (versus 9% in C) R Argentina 114 Diagnosis 69% Abalovich (1987-99) (TSH: > 5 mU/ made before (TG-Ab and/ (2002) L) pregnancy or TPO-Ab) (225) P Brazil 16 5-12 25% Sieiro Netto (TSH: > 3.6 (TG-Ab and/ (2004) mU/L) or TPO-Ab) (226) P USA 16 15.5 25 % Stagnaro- (1996-2002) (TSH: ≥ 3 (TG-Ab and/ Green mU/L) or TPO-Ab) (2005) (versus 11% (227) in C) R USA 598/17.298 < 20 31% Casey (2000-03) (3.4%) (TPO-Ab) (2007) (TSH: ≥ 3 (versus 4% (213) mU/L) in C) Foot-note to Table 14-6: The first column ‘Type of Study’ indicates whether the study was prospective (P) or retrospective (R). The second ‘Country’ indicates where the study was performed (and, in parentheses, the period during which the study was conducted). The third column ‘Hypothyroid pregnant women’: lists the number of pregnant women with a diagnosis of hypothyroidism (prevalence is indicated in percent, when available) and also the cut-off limit used for serum TSH. The fourth column ‘Timing of Screening’ shows at what time in gestation screening was carried out. The fifth column ‘Prevalence of Thyroid Antibodies’ shows the prevalence data in percent, with an indication of the type of antibody measured.
  • 39. Finally when available, the prevalence of thyroid antibodies in the control pregnant women is also indicated (versus C). (from Glinoer, Ref 212) Clinical and diagnostic features Symptoms and signs may raise clinical suspicion of hypothyroidism during pregnancy (weight increase, sensitivity to cold, dry skin, etc.) but others may go unnoticed (asthenia, drowsiness, constipation, etc.). Because many women remain asymptomatic, particular attention is required from the obstetrical care providers for this condition to be diagnosed and to evaluate more systematically thyroid function when women attend the prenatal clinic for the first time. Only thyroid function tests confirm the diagnosis. A serum TSH elevation suggests primary hypothyroidism and measurement of serum free T4 levels further distinguish between subclinical hypothyroidism (SCH) and overt hypothyroidism (OH), depending on whether free T4 is normal or clearly below normal for gestational age. Determination of thyroid antibodies, thyroperoxidase (TPO-Ab) and thyroglobulin (TG-Ab) antibodies, confirms the autoimmune origin of the disorder 228-230. Microchimerism A fascinating new topic in the field of autoimmunity and pregnancy is that of fetal microchimerism, i.e. the migration of fetal cells into maternal blood and the prolonged engraftment of fetal progenitor cells into maternal tissues. Several studies have recently confirmed that microchimerism occurs within the thyroid gland in women with Hashimoto’s and Graves’ disease. Although the biological consequences of persisting fetal microchimerism are not yet clearly understood and only beginning to be explored, fetal cells engrafted into maternal tissues may possibly play a role in the etiology of autoimmune thyroid diseases, and perhaps also in the modulation of autoimmunity during pregnancy. The contribution of natural microchimerism to the origin or exacerbation of autoimmune diseases has been widely documented, although not yet universally accepted 231-236. For instance in two recent clinical studies, the authors failed to observe an association between previous pregnancy, parity and thyroid antibodies, hence arguing against a key pathogenic role of microchimerism as a trigger of chronic thyroid autoimmunity 237, 238. Repercussions of hypothyroidism on the outcome of pregnancy Despite the known association between decreased fertility and hypothyroidism, the latter condition does not preclude the possibility to conceive. This is probably the main reason why, until a few years ago, hypothyroidism had been considered – wrongly – to be relatively rare during pregnancy 239-243. In a recent study by Abalovich at al, 34% of hypothyroid women became pregnant without thyroxine treatment: 11% of them had OH and 89% SCH 225. When hypothyroid women become pregnant and maintain the pregnancy, they carry an increased risk for early and late obstetrical complications (see Table 14-7 and Table 14-8). Table 14-7 : Pregnancy outcome associated with hypothyroidism: maternal aspects First author, year MOTHER Frequency % Type of Hypo (Ref)
  • 40. Anemia Increased 31 % OH ** Davis, 1988 (244) Postpartum Increased 4% SCH ** Leung, 1993 (222) hemorrhage Postpartum Increased 19 % OH Davis, 1988 (244) hemorrhage Cardiac Increased n. a. OH Davis, 1988 (244) dysfunction Pre-eclampsia Increased 15 % SCH Leung, 1993 (222) Pre-eclampsia Increased 22 % OH Leung, 1993 (222) Pre-eclampsia Increased 44 % OH Davis, 1988 (244) Pre-eclampsia Increased n. a. OH Mizgala, 1991 (245) Placenta Increased 19 % OH Davis, 1988 (244) abruptio Foot-note to Table 7: the percentages listed were taken (or recalculated, when possible) from the studies shown in the references. ** SCH: subclinical hypothyroidism; ** OH: overt hypothyroidism. Table 14-8 : Pregnancy outcome associated with hypothyroidism: fetal & neonatal aspects First author, year FETUS- Frequency % Type of Hypo (Ref) NEWBORN Fetal distress in increased 14 % OH ** Wasserstrum, 1995 labour (246) increased 31 % OH Davis, 1988 (244) increased 9% SCH ** Leung, 1993 (222) Prematurity/LBW* increased 22 % OH Leung, 1993 (222) increased 13 % OH Abalovich 2002 increased R.R. : 1.8 *** SCH (225) increased O.R. : 3.6 *** OH Casey, 2005 (247) Idris, 2005 (248) Breech increased O.R. : 4.7 *** Early hypo-T4 Pop, 2004 (249) presentation Cesarian section increased 29 % OH Idris, 2005 (248) Impaired intra- increased n. a. OH Blazer, 2003 (250) uterine growth Congenital increased 4% OH Leung, 1993 (222) malformations increased 6% OH Abalovich 2002 (225) increased 4% OH Leung, 1993 (222)
  • 41. Fetal death increased 12 % OH Davis, 1988 (244) increased 3% OH Abalovich 2002 increased 8% OH (225) Allan, 2000 (211) Perinatal death increased 9-20 % OH Montoro, 1981 (251) increased 3% OH Allan, 2000 (211) Foot-note to Table 8: the percentages listed were taken (or recalculated, when possible) from the studies given in the references. * LBW: low birth weight; ** SCH: subclinical hypothyroidism; ** OH: overt hypothyroidism; *** O.R.: Odds Ratio; *** R.R.: Relative Risk. Table 14-7 & Table 14-8 clearly show that both obstetrical and fetal complications occur with an increased frequency in pregnant women with hypothyroidism. As expected, these complications are both more frequent and more severe in women with OH than SCH. Most importantly, adequate treatment with thyroid hormone greatly reduces risks of a poorer obstetrical outcome 225, 244, 251-253. In the study of Abalovich, it was also shown that it was not so much the diagnosis of OH versus SCH that mattered with regard to pregnancy outcome, but primarily the adequacy of thyroxine treatment 225. When treatment was not adequate, pregnancy ended with abortion in 60% & 71% of OH & SCH women respectively, with an increased prevalence of preterm deliveries. Conversely, in hypothyroid pregnant women receiving adequate treatment, the frequency of abortions was minimal and pregnancies were carried to term without complications (see Figure 14-13). Concerning risks of premature delivery in untreated hypothyroidism women, a recent study confirmed that gravidas with high TSH levels had a greater than 3-fold increase in risk of very preterm delivery (<32 completed weeks) 227, 254. Figure 13: The graphs compare the outcome of pregnancy in 27 women with hypothyroidism known before pregnancy who received adequate thyroxine treatment during pregnancy (upper panel) with 24 women in whom thyroxine treatment was not adequately adjusted during gestation and who, hence, remained hypothyroid (lower panel). Significantly more abortions and preterm deliveries were observed in non adequately treated women, both with OH & SCH (from Abalovich, Ref 225).
  • 42. Management and therapy of gestational hypothyroidism Administration of L-thyroxine is the treatment of choice for maternal hypothyroidism, when the iodine nutrition status is adequate. Hypothyroid pregnant women require larger thyroxine replacement doses than do non-pregnant patients. Women who already take thyroxine before pregnancy usually need to increase their daily dosage by 30-50%, on average, above preconception dosage. Several reasons explain the incremented thyroid hormone requirements: the rapid rise in TBG levels resulting from the physiological rise in estrogen concentrations, the increased distribution volume of thyroid hormones (vascular, hepatic, and the fetal-placental unit), and finally the increased placental transport and metabolism of maternal T4 60, 228, 229, 255. Treatment should be initiated with a dose of 100-150 µg/day or titrated according to body weight. In non pregnant women, the full replacement thyroxine dose is 1.7-2.0 µg/kg bw/day. During pregnancy, because of the increased requirements, the full replacement thyroxine dose should be increased to 2.0-2.4 µg/kg bw/day 60-62, 229, 255, 256. In a newly diagnosed hypothyroid patient, a full replacement thyroxine dose should be instituted immediately, assuming there are no abnormalities in cardiac function. In initially severe hypothyroidism, therapy may be initiated by giving for the first few days a thyroxine dose corresponding to two times the estimated final replacement daily dose, in order to normalize more rapidly the extra-thyroidal thyroxine pool. In women who already take thyroxine before conception, the need to adjust the preconception daily dosage may become manifest as early as by 4 to 6 weeks gestation, hence justifying the early adaptation of thyroid hormone replacement to ensure that maternal euthyroidism is maintained during the first months of pregnancy. An alternative (recommended by some thyroidologists) is to anticipate the expected increase in serum TSH by raising the thyroxine dose already before conception or as soon as the pregnancy is confirmed. Among the possible preventive strategies to avoid the risk of maternal hypothyroidism during early gestational stages, it can be recommended to adjust the preconception thyroxine dose with the aim to maintain serum TSH near the low-normal range 257, 258. It is important to note that 25% of hypothyroid women who are able to maintain a normal serum TSH level in the first trimester, and 35% of those who maintain a normal serum TSH level until the second trimester without increasing their daily dosage, will still require an increment in thyroxine replacement during late gestation to remain euthyroid 229, 248, 259. If a pregnancy is planned, patients should have thyroid function tests measured soon after the missed menstrual period. If serum TSH is not increased at that time, tests should be repeated at 8-12 weeks and then again at 20 weeks, as the increase in hormone requirements may not become apparent until later during gestation. The magnitude of thyroxine increment during pregnancy depends on the etiology of hypothyroidism, namely the presence or absence of residual functional thyroid tissue. Women without residual functional thyroid tissue (after radioiodine ablation, total thyroidectomy, or due to congenital agenesis of the gland) require a greater increment in thyroxine dosage than women with Hashimoto’s thyroiditis, who usually have some residual thyroid tissue. As a simple rule of thumb, it has been suggested that the increment in thyroxine can be based on the initial degree of TSH elevation. For women with a serum TSH between 5-10 mU/L, the average increment in thyroxine dosage is 25-50 µg/day; for those with a serum TSH between 10-20 mU/L, 50-75 µg/day; and for those with a serum TSH >20 mU/L, 75-100 µg/day 229. Serum free T4 and TSH levels should be measured within one month after the initiation of treatment. The overall aim is to achieve and maintain normal free T4 and TSH levels throughout pregnancy. Ideally, thyroxine doses should be titrated to reach a serum TSH value <2.5 mU/L (see Table 14-9). As discussed already, because it is sometimes difficult to correctly interpret the results of free T4 and TSH measurements in the context of pregnancy, it is useful to optimize monitoring of treatment by establishing laboratory-specific reference ranges for serum free T4 and trimester-specific reference
  • 43. ranges for serum TSH. Once parameters of thyroid function have been normalized by treatment, they should be monitored every 6-8 weeks. If they remain abnormal, thyroxine dosage should be adjusted and tests repeated after 30 days, and so on until normalization. After parturition, most patients need to decrease thyroxine dosage, over a period of ~4 weeks postpartum. It should also be remembered that women with thyroid autoimmunity features are at risk of developing postpartum thyroiditis, a syndrome that may justify differences in the pre- and post-pregnancy thyroxine requirements. It is therefore important to continue monitor thyroid function tests for at least during six months after the delivery 260. A recent study has examined how closely the management of hypothyroidism in the general pregnancy population satisfies recently issued guidelines 261. This observational retrospective study concerned 389 women, at 5 recruitment centers in the USA. The results showed that 43% of serum TSH levels measured in 1st trimester were at or above the recommended upper limit of 2.5 mU/L. In 2nd trimester, 33% of serum TSH measurements were at or above the recommended upper limit of 3.0 mU/L. When using a less restrictive upper limit, defined as a serum TSH value above the 98th percentile of normal, the data showed that 20% of serum TSH values in 1st trimester and 23% in 2nd trimester were above the upper normal limit. The authors concluded that future strategies should focus on more effectively monitoring thyroxine treatment during pregnancy. Table 9. Thyroxine dosage needed for maintaining normal serum TSH concentration before and during pregnancy in patients with primary hypothyroidism* Patients with Hashimoto's disease ( n Patients with thyroid ablation ( n = = 15 ) 18 ) Before During Before During *p<0.01. (from Kaplan, Ref 61) T4 dose (μg/day) 111 ± 25 139 ± 52 114 ± 33 166 ± 64 * T4 dose 1.7 ± 0.6 1.9 ± 0.9 1.8 ± 0.5 2.3 ± 0.8 * (μg/kg/day) Serum TSH 2.0 ± 1.8 1.8 ± 1.1 1.5 ± 1.3 1.9 ± 1.1 (mU/L) Fetal-neonatal consequences of maternal hypothyroidism Role of thyroid hormone during fetal brain development Alterations of thyroid function in newborns soon after birth have been recognized to be associated with neurodevelopment abnormalities for over a century. This led to two major concepts in endocrinology, namely those of endemic cretinism due to severe iodine deficiency and sporadic congenital hypothyroidism (CH), which, in turn, led to the development in the late 1970s of systematic screening programs for the early diagnosis and treatment of sporadic CH. During the largest part of the 20th century, it was considered that the developing brain did not need thyroid hormone until after birth and this concept was reinforced by the notion of an efficient uterine-placental barrier, preventing the transfer of physiologically relevant amounts of maternal thyroid hormone to the fetal compartment. At the end of the 1980s, however, it was shown that thyroid hormone (TH) of maternal origin was present in human fetal blood up to birth, and also that maternal TH had a protective effect on experimentally-induced CH in animal models 83-85. Recent availability of highly sensitive assays for the measurement of minute amounts of TH in fetal tissues have allowed to show that physiologic amounts of free T4 are present in coelomic and amniotic fluids surrounding the developing embryo already in first trimester. Also, specific nuclear receptors
  • 44. are present in fetal brain as early as ~8 weeks post-conception 262-267. The ontogenic pattern of TH concentrations and activity of iodothyronine deiodinases have been investigated in different cerebral areas of human fetuses as early as 11-18 weeks post- conception. Results of these studies have indicated the presence of increasing T4 and T3 concentrations in fetal brain, as well as a complex interplay between changing activities of the specific ‘D2’ and ‘D3’ iodothyronine deiodinases during gestation. This dual enzymatic system is currently interpreted to represent a regulatory pathway, allowing to fine tune the availability of T3 required for normal brain development and avoid the presence of excessive amounts of T3. In summary, a large body of both human and experimental evidence strongly suggests that thyroid hormone is an important factor contributing to normal fetal brain development 268-273. At early stages of pregnancy, the presence of TH in fetal structures can only be explained by the transfer of maternal TH to the fetal compartment, since fetal thyroid hormone production does not become efficient until mid-gestation. Clinical studies on the role of maternal hypothyroidism for the psycho-neurological outcome in the progeny Because of the heterogeneity of what is commonly referred to as gestational hypothyroidism, different clinical conditions must be considered. Thyroid insufficiency varies widely with regard to time of onset (first trimester versus later), degree of severity (SCH versus OH), progressive aggravation with gestation time (depending on the cause), and adequacy of treatment. To reconcile these variable clinical conditions into a global view of the repercussions of maternal hypothyroidism on the progeny is difficult. However, a common pattern clearly emerges. Several clinical studies have investigated the psychological and intellectual outcome in the offspring of pregnant women with thyroid insufficiency, both in conditions of hypothyroidism with an adequate iodine nutritional status and women with mild- moderate iodine deficiency. Overall, the results show that there is a significantly increased risk of impairment in neuro-psychological developmental indices, IQ scores, and school learning abilities in the offspring of untreated hypothyroid mothers. Three decades ago, Evelyn Man and colleagues published a series of articles suggesting that children of mothers with inadequately treated hypothyroidism had significantly lower IQs than those born to adequately treated patients or normal controls. These pioneering data did not gain much clinical attention, probably because the prevailing dogma, at that time, was that maternal TH did not cross the placenta 274-276. The first large-scale prospective study on outcome of children born to mothers with thyroid deficiency was reported by Haddow et al. in 1999 224. Sixty two women were identified retrospectively, who had hypothyroidism around mid-gestation with elevated serum TSH and low free T4. The children of these women were matched with 124 control children and all underwent extensive neuropsychological testing at ~8 years of age. Main results showed that the mean full-scale IQ of children born to mothers with untreated maternal thyroid disease was 7 IQ points lower than the mean IQ of children born to both controls and hypothyroid but thyroxine-treated mothers (see Table 14-10). Furthermore, three times as many children born to mothers with untreated hypothyroidism had IQs that were 2 standard deviations below the mean IQ of the controls. The conclusion was that undisclosed (and hence untreated) hypothyroidism occurring during the first half of pregnancy (and presumably prolonged thereafter) was associated with a risk of a poorer outcome in the progeny and a 3-fold increased predisposition for having learning disabilities later in life. It should however be noted that in this study, the severity of maternal hypothyroidism varied from OH to probable SCH. Table 14-10. IQ scores in children born to mothers with hypothyroxinemia
  • 45. Children born to Healthy control Mothers with hypo- P value mothers T4 Data taken from Haddow, Ref 224 Average IQ score 107 (overall) 103 0.06 Average IQ score 107 (untreated) 100 0.004 Average IQ score 107 (T4-treated) 111 0.259 IQ scores > 2 SD below the mean of 4% 13 % 0.08 controls Although still incompletely published, a large set of data was reported at the 2004 annual meeting of the American Thyroid Association by Rovet et al. 277. The interest of this remarkable work is double. First, the authors investigated children born to hypothyroid mothers who had been treated during pregnancy, but in whom thyroxine administration remained suboptimally adapted (mean TSH levels between 5-7 mU/L). Second, children were tested with extremely refined techniques and followed up to 5 years of age. Results showed that some components of intelligence were affected, while others not. At preschool age, the study-case children had a mild reduction in global intelligence that was inversely correlated with third trimester’s maternal TSH. On the other hand, there was no negative impact on language, visual-spatial ability, fine motor performance, or preschool ability. The conclusion was that the offspring of women with suboptimal treatment of maternal hypothyroidism may be at risk for subtle and selective clinically relevant cognitive deficits, which depend specifically on severity and timing of inadequate maternal thyroid hormone availability. An interesting - although still intriguing - issue is that of potential repercussions for fetal development of isolated hypothyroxinemia in pregnant women. The first study to deal specifically with this issue was published by Pop et al. in 1999. The authors investigated development outcome in children born to mothers who had early (i.e. 1st trimester) low serum free T4 levels without TSH elevation 278. These women corresponded to the lowest 10th decile of free T4 values at 12 weeks gestation (<10.4 pMol/L) among 220 apparently normal pregnancies. Main results suggested that early maternal free T4 was associated with a lower developmental index in the children at 10 months of age. The study was criticized because the scoring method used was not discriminant enough and the study did not include a control group. The same group of authors published later a 2nd study based on similar selection criteria, but with a larger cohort and a control group, and also more refined motor and mental evaluations in infants at 1 and 2 years of age 279. Main results showed that children of mothers with prolonged hypothyroxinemia (until 24 weeks or later) had an 8-point to 10-point deficit on mental and motor developmental scales. Of interest, those infants of women who presented early hypothyroxinemia but recovered spontaneously normal free T4 levels during later gestation had a normal development, suggesting that prolonged hypo-T4 was needed to impair fetal neuro-development. Finally in 2006, the same group of investigators confirmed their earlier findings in another study that examined the neurobehavioral profile of neonates born to mothers with isolated early hypothyroxinemia 280. The results indicated that neuro-developmental difficulties could be identified as early as 3 weeks of age. The significance of early isolated maternal hypothyroxinemia was also investigated by Casey et al. in a large-scale study of >17,000 women 213. The authors identified 233 women (1.3%) with isolated low free T4 in 1st half of pregnancy. Assessing adverse effects of this biochemical abnormality on parameters of pregnancy outcome, the authors were unable to
  • 46. identify any excessive adverse pregnancy outcome feature and concluded that their findings “cast further doubt on the biologic significance isolated maternal hypothyroxinemia”. Finally, a study is ongoing in Wales (under the leadership of John Lazarus) on this topic and, from preliminary data disclosed at recent meetings, it appears that this condition (isolated hypo-T4 with a normal serum TSH) seems to be relatively frequent but its consequences are still unclear. As already mentioned above, in the studies by Pop et al. referred to above, it is not clear why these women had a low free T4 and also why the majority recovered spontaneously a normal thyroid function after the 1st trimester of gestation. Our current opinion is that one must distinguish between isolated low free T4 and low free T4 in the contest of hypothyroidism, especially for the purpose of defining who should benefit from early treatment with thyroxine. This opinion is shared by Mitchell & Haddow who recently showed that in hypothyroid pregnant women, low free T4 concentrations were almost never observed without a concomitant elevation in serum TSH 281. Clinical studies of the psycho-neurological outcome in the progeny associated with maternal hypothyroidism due to iodine deficiency Consequences of maternal hypothyroidism on the progeny must be considered separately because iodine deficiency (ID) exposes both mother and fetus to thyroid underfunction 86. In 1994, Bleichrodt & Born published the results of a meta-analysis of 19 studies of infants’ outcome in relation to ID 282. The main result was to demonstrate a shift in frequency distribution of IQ towards lower values, with a mean overall reduction of 13.5 IQ points in both neuro-motor and cognitive functions. Because this meta-analysis encompassed public health conditions with more or less severe iodine deficiency, the results cannot be fully extrapolated to mild-moderate ID. Therefore, the main results of a series of clinical studies (reported between 1989-1996) that have investigated the late outcome in children born to mothers who reside in areas with only mild-moderate ID were examined in a review article by Glinoer & Delange 86. Main results are summarized in Table 14-11, showing that many of these infants do present school learning difficulties. A recent publication dealing with the outcome of children of mothers exposed to mild- moderate ID during pregnancy was performed in Sicily by Vermiglio et al. 283. The authors showed that these children had a greater than 10 point average deficit in global IQ, compared with children born to mothers from another area in Sicily without ID. Furthermore, they reported the presence of attention deficit & hyperactivity disorder (ADHD) in 69% of children born to the mothers who presented hypothyroxinemia during early gestation. Finally, Kasatkina et al. studied children born to mothers in whom gestational low free T4 values were corrected by thyroxine administration and showed that it improved the neuro- intellectual prognosis of the offspring evaluated at the ages of 6, 9, and 12 months 284. Table 14-11. Neuropsychiatric and intellectual deficits in infants and schoolchildren born to mothers residing in conditions with mild to moderate iodine deficiency AUTHOR REGION TESTS MAIN FINDINGS (Ref ) Data adapted from Glinoer, Ref 86 Locally adapted: - BAYLEY Lower psychomotor and mental Bleichrodt SPAIN - McCARTHY development (285) - CATTELL ITALY BENDER-GESTALT Low perceptual integrative motor ability Vermiglio (286) (Sicily) & neuromuscular and neuro-sensorial
  • 47. AUTHOR REGION TESTS MAIN FINDINGS (Ref ) abnormalities ITALY WECHSLER Low verbal IQ, perception, motor and Fenzi (287) (Tuscany) RAVEN attentive functions Vitti (288) ITALY WISC Lower velocity of motor response to Aghini- (Tuscany) Reaction time visual stimuli Lombardi (289) Verbal, pictorial learning INDIA Lower learning capacity Tiwari (290) tests, Tests of motivation BENDER-GESTALT Retardation in psychomotor IRAN Azizi (291) RAVEN development Comments and perspectives Clinical studies discussed in the sections above were carried out in conditions where thyroid underfunction was associated with either iodine deficiency or thyroid autoimmunity during pregnancy. Together, they clearly underline the notion that when thyroid failure occurs during pregnancy, this abnormality may be associated with impairment in the normal development of the fetal brain. Alterations in neuro-psycho-intellectual outcome in the progeny may ultimately result from a combination of detrimental effects related to maternal hypothyroidism per se, as well as from impaired fetal thyroid function per se, or the two in combination. With regard to maternal hypothyroidism, detrimental effects of hypothyroxinemia are predominant when present already during early gestational stages, although deleterious effects may also be due to maternal hypothyroidism occurring during late gestational stages and perhaps also to hypothyroidism taking place (or persisting) during the postpartum period, indirectly through a ‘lesser well-being’ status, which is so characteristic of patients with unrecognized hypothyroidism. One important lesson to be learned from recent studies is that an altered neuro-psycho-intellectual development may occur in offspring even in the presence of only mild and perhaps transient maternal hypothyroxinemia, and obviously in the absence of detectable abnormalities of neonatal thyroid function after birth. In most clinical circumstances where a woman’s thyroid function is defective, hypothyroxinemia is not restricted to 1st trimester and hypothyroidism tends to worsen as gestation progresses, especially when left undiagnosed and untreated. The fetus may therefore be deprived of adequate amounts of thyroid hormones in the early stages of brain development, as well as during later neurological maturation and development, thereby reinforcing the negative consequences of early maternal hypothyroxinemia. Thus, any delay in diagnosing and treating maternal hypothyroidism may ultimately cost ‘IQ’ points to the progeny, with the educational, socioeconomic, and public health consequences that may be foreseen. Globally in maternal-fetal thyroid disease, three sets of clinical disorders ought to be considered, illustrated schematically in Figure 14-14. For infants with a defect in thyroid ontogeny leading to congenital hypothyroidism, the participation of maternal hormones to the fetal T4 circulating environment remains unaffected, and therefore the risk of brain damage results exclusively from insufficient fetal thyroid hormone production. In contrast, when only the maternal thyroid gland is deficient, such as in women with autoimmune hypothyroidism, it is both the severity and temporal occurrence of maternal underfunction that drive the resulting consequences for fetal neuronal development. Finally in iodine deficiency, both maternal and fetal thyroid functions are affected, and it is the degree and precocity of iodine deficiency during pregnancy that drives the potential repercussions for fetal neurological development 86.
  • 48. Figure 14: Schematic and integrated representation of the three sets of clinical conditions that may affect thyroid function in mother alone, fetus alone, or both (i.e. the fetal-maternal unit), to show how the relative contributions of an impaired maternal and/or fetal thyroid function may eventually lead to alterations in fetal thyroxinemia during in utero development. (from Glinoer & Delange, Ref 86) Screening for hypothyroidism during pregnancy There are no recommendations for universal screening for thyroid dysfunction in women before or during pregnancy. As the overall benefits of screening for thyroid dysfunction (primarily hypothyroidism) have not yet been universally justified by current evidence-based medicine, recent international guidelines have recommended ‘aggressive’ case finding among the following groups of women who are at high risk, preferably already prior to pregnancy or in early gestation (see Table 14-12) 1. Table 14-12: High risk women for whom screening is recommended Women with a history of hyperthyroid or hypothyroid disease, postpartum thryoiditis, thyroid lobectomy, and women who already take thyroxine prior to concenption. Women with a family history of thyroid disease. Women with a goiter. Women with thyroid antibodies (when known).
  • 49. Women with symptoms or clinical signs suggestive of thyroid underfunction or overfunction, including anemia, elevated cholesterol, and hyponatremia. Women with type I diabetes. Women with other autoimmune disorders. Women with a prior history of head and neck irradiation. Women with infertility should have screening with TSH as part of their infertility work-up. Women with a prior history of miscarriage and preterm delivery. Foot-note to Table 14-12: These are the recommendations made by the ad hoc committee of the Endocrine Society in the Clinical Practice Guidelines (from Abalovich, Ref 1). Among possible screening algorithms, the following scheme has been proposed and is outlined in Figure 14-15. during early gestation (12-20 wks) TPO-Ab (+ TG-Ab?) + Free T4 + TSH if Ab neg. if Ab+/TSH<2 if Ab+/TSH 2-4 if TSH > 4 or fT4 below Nl if free T4 is low- normal for G. A. do nothing do nothing but control TSH and treat with l-T4 & free T4 at 6 months follow during PP and follow during PP treat with l-T4 & follow during PP Figure 15: An algorithm for systematic screening of thyroid autoimmunity and hypothyroidism during pregnancy based on the determination of thyroid antibodies (Ab), serum TSH and free T4 concentrations during the first half of gestation. GA = gestational age; NL = normal limits; PP = postpartum (from Glinoer ; Ref 208). The first step in the algorithm is to measure serum TSH and thyroid antibodies in early gestation. Because isolated hypothyroxinemia may occur in some women (without concomitant rise in serum TSH), it is reasonable to include systematically a free T4 determination. Ideally, both TG-Ab and TPO-Ab should be determined; however, if for economical reasons only one antibody can be measured, then it is preferable to measure TPO-Ab because it yields the best diagnostic score. When serum TSH is elevated or free T4 clearly below normal, and irrespective of the presence (or absence) of thyroid autoimmunity (TAI), women should be considered to have thyroid underfunction and treated with thyroxine.
  • 50. The next step concerns those women with TAI and normal thyroid function. We propose to base the medical attitude on serum TSH levels during early pregnancy. When serum TSH is <2.5 mU/L (most frequently associated with low antibodies titers and normal free T4 levels), thyroxine treatment is not systematically warranted, and serum TSH and free T4 should be monitored later during gestation. For women with TAI and a serum TSH that lies within the normal range in early gestation, but is already slightly shifted to higher ‘normal’ values, i.e. between 2.5-4.0 mU/L (most frequently associated with higher antibody titers and low-normal free T4 levels), obstetric care providers should consider thyroxine treatment. It is important to keep in mind that serum TSH is down-regulated under the influence of peak hCG values in the 1st half of gestation, and also that the thyroid deficit tends to deteriorate as gestation progresses in TAI-positive women. Because the potential deleterious effects, for both mother and progeny, are not due to high serum TSH per se but to low free T4 concentrations, clinical judgment should be based on serum free T4. If low or low-normal for gestational age, thyroxine treatment is probably justified. In daily practice, when such a scheme is systematically applied, most - if not all - of the pregnancies followed are successful and uneventful 225, 292. Even though more prospective studies are needed to assess the final clinical relevance of the proposed scheme, the recent study of Negro et al. provided strong arguments in favor of early thyroxine administration in women with AITD and normal thyroid function during early gestation 202. Based on many indirect arguments, it is our personal belief that no harm can be done and that thyroxine treatment can only be beneficial, in such conditions, for both the patient and offspring. Finally, systematic screening for AITD during early pregnancy also allows to delineating women who are prone to developing thyroid dysfunction after parturition. Thus, even when no specific treatment is warranted during gestation, systematic screening is useful to clinicians for organizing the monitoring of potential postpartum thyroid dysfunction 293, 294. Recommendations and ‘take home’ messages Because of the high frequency of autoimmune thyroiditis in young women, because subclinical hypothyroidism (SCH) often remains undiagnosed, because potential obstetric repercussions are associated with un(der)treated hypo-thyroidism, and finally because of the consequences of maternal hypothyroxinemia on fetal development, there is a justification to propose systematic screening for autoimmune thyroiditis and hypothyroidism in pregnancy. SCH has been shown to be associated with an adverse outcome in both mother and offspring. Therefore, maternal hypothyroidism should be avoided. Women with autoimmune thyroiditis who are euthyroid in early stages of pregnancy are still at risk of developing hypothyroidism later; therefore, their serum TSH levels should be monitored. Subclinical hypothyroidism (serum TSH concentration above the upper limit of the reference range with a normal free T4) has been shown to be associated with an adverse outcome for both the mother and offspring. Thyroxine treatment has been shown to improve obstetrical outcome, but has not been proved to modify long term neurological development in the offspring. Given that potential benefits outweigh potential risks, thyroxine replacement is recommended in women with SCH. If hypothyroidism has been diagnosed before pregnancy, it is recommended to adjust rapidly preconception thyroxine doses to reach a TSH level prior to pregnancy not higher than 2.5 mU/L. The thyroxine dose often needs to be incremented by 4-6 weeks gestation, and may require a 30-50% increment in dosage. If overt hypothyroidism is diagnosed during pregnancy, thyroid function tests should be normalized as rapidly as possible. Thyroxine doses should be titrated to rapidly reach and thereafter maintain serum TSH concentrations of less than 2.5 mU/L in the first trimester (or
  • 51. 3 mU/L in 2nd & 3rd trimesters) or to trimester-specific ranges. Thyroid function tests should be re-measured within 30-40 days. After delivery, most hypothyroid women need a decrease in the thyroxine dosage they received during pregnancy. Finally, there is a consensus among obstetrical providers and endocrinologists against advising to interrupt a pregnancy, even when hypothyroidism has been diagnosed late during pregnancy.
  • 52. THYROTOXICOSIS One of the challenges for endocrinologists and obstetric care providers remains the evaluation and management of hyperthyroidism in the pregnant patient, and in particular that of Graves' disease (GD). Hyperthyroidism during pregnancy is relatively uncommon, with a prevalence estimated to range between 0.1% and 1% (0.4% clinical & 0.6% subclinical) 46, 295-299. Causes of thyrotoxicosis include those found in the general population, as well as others that occur specifically during pregnancy. Etiologies such as single toxic adenoma, toxic multinodular goiter, subacute or silent thyroiditis, iodide-induced thyrotoxicosis, and thyrotoxicosis factitia are uncommon during pregnancy. Molar disease should always be considered as it can potentially lead to severe thyrotoxicosis, particularly in pregnant women with a pre-existing autonomous or nodular goiter. However, since uncomplicated hydatidiform mole is easily diagnosed in early gestation, it rarely leads to severe thyrotoxicosis 34, 35, 300, 301. Other extremely rare causes of hyperthyroidism (described recently as isolated cases) include hyperplacentosis and struma ovarii 302-304. In women in the childbearing age, the most common cause of hyperthyroidism is GD, as this etiology accounts for 85% of clinical hyperthyroidism in pregnancy. Another cause of hyperthyroidism results directly from the stimulatory action of hCG on the thyroid and this etiology is associated with transient hyperthyroidism in the first half of gestation. Although the overall prevalence of hCG-induced hyperthyroidism is greater than that of GD, it is usually much less severe clinically and seldom requires treatment. This syndrome is referred to as gestational transient thyrotoxicosis (GTT) or gestational hyperthyroidism and differs fundamentally from GD in that it is not of autoimmune origin and, furthermore, the course, fetal risks, management and follow-up of both entities are entirely different 6, 25, 42, 44, 46, 50, 228, 297. Clinical diagnosis of hyperthyroidism in pregnancy Even though the historical clues and physical findings are the same in pregnant and non pregnant patients, the diagnosis of thyrotoxicosis may be difficult to make clinically during pregnancy. Non specific symptoms such as fatigue, anxiety, tachycardia, heat intolerance, warm moist skin, tremor and systolic murmur may be mimicked by normal pregnancy. Alternatively, presence of goiter, ophthalmopathy and pretibial myxoedema obviously points to the suspicion of GD (see Table 14-13). A useful symptom of hyperthyroidism is that, instead of the customary weight gain, patients may report weight loss or, even more frequently perhaps, absence of weight gain despite an increased appetite (unless there is also excessive vomiting). Nausea (morning sickness) occurs frequently during normal pregnancy. However, the occurrence of hyperemesis gravidarum accompanied by weight loss must always raise the suspicion of hCG-induced hyperthyroidism. Table 14-13 Clinical features suggesting the possibility of hyperthyroidism due to Graves' disease in a pregnant patient Historical 1. Prior history of hyperthyroidism or autoimmune thyroid disease in the patient or her family. 2. Presence of typical symptoms of hyperthyroidism including weight loss (or failure to gain weight), palpitations, proximal muscle weakness, or emotional lability. 3. Symptoms suggesting Graves' disease such as ophthalmopathy or pretibial myxedema. 4. Thyroid enlargement. 5. Accentuation of normal symptoms of pregnancy such as heat intolerance, diaphoresis, and fatigue. 6. Pruritis. Physical examination
  • 53. 1. Pulse rate > 100. 2. Widened pulse pressure. 3. Eye signs of Graves' disease or pretibial myxedema. 4. Thyroid enlargement especially in iodine sufficient geographical areas. 5. Onycholysis. Laboratory diagnosis Patients suspected of having hyperthyroidism require measurement of serum TSH, T4 and T3 levels, and anti-TSH receptor antibodies (TRAb). Virtually all patients with significant symptoms have a serum TSH <0.1 mU/L, as well as concurrent elevations in serum free T4 and T3 levels. However, interpretation of thyroid function tests must take into account the hCG-mediated decrease in serum TSH that occurs during pregnancy. Near the end of 1st trimester, at the time of peak hCG values, serum TSH levels may be transiently lowered to values below 0.4 mU/L in ~20% of euthyroid women 3, 5, 6, 20, 25, 36, 41, 73, 304, 305. Thus, the degree and duration of TSH suppression (mainly but not only) in 1st trimester must be considered in making the differential diagnosis. Concerning T4 and T3 levels, the pitfalls and necessary caution in the interpretation of serum free T4 and T3 have been discussed earlier (see the section on thyroid function parameters in normal pregnancy). Patients with GD usually have positive thyroid antibodies (TG-Ab and TPO-Ab) and, therefore, antibody presence should alert the clinician to the possibility that autoimmune thyroid disease is the cause of symptoms evoking hyperthyroidism. Most patients with GD have detectable TRAb. Since TRAb production tends to undergo immunologic remission during the second half of pregnancy, detection of TRAb may depend upon gestational age at determination 306, 307. Presence of TRAb in 1st trimester is highly useful in helping make the differential diagnosis between GD and other causes of gestational hyperthyroidism. Clinical aspects of the management of Graves’ disease in pregnancy Three clinical situations are important to consider: a) women with active GD diagnosed before pregnancy and who receive antithyroid drug (ATD) treatment; b) women who have had GD and are in remission or considered cured after prior treatment; and finally c) women in whom the diagnosis of GD has not been established before the onset of pregnancy, but who present positive TRAb. Control of hyperthyroidism and pregnancy outcome An important clinical concept is that the risk of complications for mother and child is directly related to the duration and adequate control of maternal hyperthyroidism (see Table 14-14). The most common complication is gestational hypertension, with a risk of preeclampsia that is ~5-fold greater in women with uncontrolled hyperthyroidism. Other obstetrical complications include miscarriage, fetal malformation, placenta abruptio, preterm delivery and low birth weight 297, 305, 306, 308-310. With regard to the risk of miscarriage in women with elevated thyroid hormone levels, a recent study showed that women with a genetic resistance to thyroid hormone (hence, who were euthyroid but had elevated T4 levels) experienced a significantly increased miscarriage rate compared to normals 311. The hypothesis was that the elevated maternal thyroid hormone levels caused hyperthyroidism in the fetus not carrying the gene for thyroid hormone resistance. Congestive heart failure may occur in women left untreated or treated only for a short period of time in the presence of gestational hypertension or operative delivery 304, 312. In a recent study from Australia, the outcome of pregnancy was evaluated in women with unrecognized maternal GD 313.
  • 54. Results showed severe prematurity (mean gestational age of 30 weeks at delivery) associated with very low birth weight (<2 Kg) and neonatal hyperthyroidism requiring treatment with ATD. In contrast, for those patients in whom the diagnosis was made early and treatment started promptly, the outcome was excellent. In a report of a family presenting non-autoimmune hyperthyroidism due to an activating TSH receptor gene mutation, it was recently shown that premature delivery and low birth weight were consistent features associated with this unusual cause of thyrotoxicosis 314. Finally, in another study of 230 pregnant women with GD in Japan, no adverse impact on the outcome of pregnancy was found in patients with adequately treated Graves' disease 315. Table 14-14: Adverse pregnancy outcome and lack of control of maternal hyperthyroidism Poor control Less than Adequate Ref N° adequate control control Preeclampsia 14-22% 7% 289 CHF * 60% 3% 288 Thyroid storm 21% 2% 285 Preterm delivery 88% 25% 8% 288 LBW ** 23% 10% 290 Foot-note to Table 14-14: * CHF: congestive heart failure; ** LBW: low birth weight (< 2,500 g) Measurement of TSH-receptor antibodies GD is an autoimmune disease and it is therefore important to consider that the production of TRAb may fluctuate during pregnancy and, in turn, influence the clinical course of the disease. Since GD tends to undergo immunologic remission during gestation, TRAb detection may depend upon gestational age at measurement 306. The classical course of Graves’ disease during pregnancy frequently encompasses exacerbation of hyperthyroidism during 1st trimester and a gradual improvement in the 2nd half of gestation. Maternal production of TRAb may remain elevated even after a prior thyroidectomy or thyroid ablation using radioiodine, or the apparent cure of the disease by antithyroid drug (ATD) therapy given several years before pregnancy. In euthyroid pregnant women who have previously received ATD for GD but who are currently not receiving ATD treatment, the risk of fetal/neonatal thyrotoxicosis is negligible and, therefore, systematic measurement of TRAb is not mandatory. For a euthyroid pregnant woman (with or without thyroid hormone replacement therapy) who has previously been treated with radioiodine or undergone thyroid surgery for GD, the risk of fetal/neonatal thyrotoxicosis depends upon the level of TRAb produced by the mother. As a result, TRAb should be measured in early pregnancy to evaluate this risk. For pregnant women who take ATD for the treatment of active GD (assuming that ATD was started before or in early pregnancy), TRAb should be measured in the first and last trimesters. If TRAb titers have not substantially decreased during the 2nd trimester, the possibility of fetal thyrotoxicosis should be considered 46, 59, 228, 316. Radetti et al. showed that TRAb’s maternal transfer to the fetus in a hyperthyroid pregnant woman with active GD caused a marked increase in the fetal/maternal TRAb ratio 317. Thus, the fetal-placental unit gradually concentrates proportionally larger fractions of thyroid stimulating antibodies from maternal blood, particularly during the second half of gestation, hence underlining the importance to systematically search for fetal thyroid dysfunction in all clinical conditions where the mother may produce large amounts of TRAb. In a recent study by Peleg et al., it was confirmed that neonatal thyrotoxicosis occurred only in infants of mothers with high TRAb titers 318. As indicated above, hyperthyroidism due to Graves' disease usually tends to improve gradually during gestation, although exacerbations can be observed in the first weeks.
  • 55. Several reasons may help explain this spontaneous improvement: the partial immunosuppressive state characteristic of pregnancy with progressive decrease in TRAb production; the marked rise in maternal serum TBG levels that tends to reduce serum free T4 & T3 fractions; obligatory iodine losses specific of pregnancy that may, paradoxically, constitute an advantage for women with GD; changes in cytokine production between normal and GD pregnant women may also help explain the transient remission of the disease; and finally, a suggestion was made that the balance between TRAb’s blocking and stimulating activities may be modified in favor of blocking antibodies 319-322. The reality of the latter finding, however, has been recently denied in another study from Japan 323. Among possible reasons for an exacerbation of thyrotoxicosis in women with GD during early pregnancy, one must keep in mind the potential coincidental stimulatory effect of high hCG levels, and this has recently been shown to occur in perhaps as many as 26% of such women 324. Since TRAb may contain a mixture of auto-antibodies with different action types on the TSH receptor, there is room for confusion. All antibodies that can compete with TSH for binding to the TSH receptor are identified as thyrotropin-binding inhibitory immuno-globulins (TBII). These antibodies are measured using commercially available kits that record the percentage of inhibition of TSH binding to a membrane preparation of human or porcine TSH receptors. These assays do not measure the ability of antibodies to stimulate the TSH receptor, although binding and stimulation frequently go in parallel. Therefore, these assays are often used as surrogates for assays of TSH receptor stimulating antibodies. Antibodies that stimulate the receptor can be measured by their ability to stimulate cAMP production in a preparation of cell membranes containing the TSH receptor. Such assays are specific for the pathogenic antibody of GD, but they are not generally available in hospital or commercial laboratories. Some antibodies bind to the TSH receptor and inhibit the stimulating activity of TSH. Such antibodies may be clinically significant since they can cause hypothyroidism (including in the fetus), but they are usually measured only in a research setting. Their assay depends upon their ability to reduce cAMP production induced by TSH, in the setting of the stimulating assay described above 325. Therapeutic considerations Antithyroid drugs (ATD) are the main treatment for GD during pregnancy. The overall goal of therapy is to control maternal disease by maintaining the patient at a high euthyroid or borderline hyperthyroid level, while minimizing the risk of fetal hyperthyroidism or hypothyroidism by using the smallest possible dose of ATD. The treatment of GD with ATD in pregnancy has recently been reviewed in detail in several review articles by Marcos Abalovich et al., Jorge Mestman, David Cooper, Susan Mandel & David Cooper, Shane LeBeau & Susan Mandel, and Helen Marx et al. 1, 297, 299, 304, 326, 327. 1. Antithyroid drugs Propylthiouracil (PTU), methimazole (MMI) and carbimazole (CMI) have been used during gestation. These medications inhibit thyroid hormone synthesis via inhibition of iodine organification and iodotyrosine coupling. Pregnancy itself does not appear to alter significantly the pharmacokinetics of ATD and both PTU and MMI (or CMI) appear equally effective 328. The ATD dosage should be maintained at a minimum and drugs discontinued, when feasible (often possible after six months of gestation). Combined administration of ATD and thyroxine to the mother should be avoided, since trans-placental passage of ATD is high while negligible for thyroid hormones and, hence, thyroxine will not protect the fetus from ATD-induced hypothyroidism. All ATD cross the placenta and may therefore inhibit fetal thyroid function. PTU is more water soluble and more extensively bound to albumin at physiologic pH than MMI. Theoretically therefore, treatment with MMI may result in an increased trans-placental passage relative to
  • 56. PTU. These facts have led authors to recommend preferentially the use of PTU during pregnancy and lactation, based on the concept that the fetus and/or infant might be at higher risk of developing hypothyroidism when women receive MMI. From all the available information taken together, however, differential placental transfer of PTU and MMI appears unlikely and by itself does not support the preferential use of PTU versus MMI. Furthermore, MMI (or CMI) is commonly used in pregnancy in countries where PTU is not available (for instance, in Japan and several European countries), without particular problem. Therefore, the recommendation for the sole use of PTU does not appear to be justified. 76, 329-335. General guidelines for the treatment of Graves’ disease in pregnancy are summarized in Table 14-15. The principle of therapy is to administer the lowest dose of ATD needed for controlling clinical symptoms. Maintaining a mild degree of hyperthyroidism is acceptable as long as the patient tolerates this condition and pregnancy progresses satisfactorily. Patients should be followed closely, with careful monitoring of weight gain, heart rate, etc. A typical starting dose of ATD is 50-100 mg PTU twice daily (or the equivalent dosage for MMI/CMI). When both types of ATD are available, most clinicians prefer to use PTU than MMI. Monitoring ATD treatment monthly is necessary. After control of thyrotoxicosis, it is often possible to reduce the dose of ATD. The decision as to the maximal safe ATD dose during pregnancy is somewhat arbitrary, since the results vary with individual maternal-fetal pairs. Limits as widely variable as 150-450 mg/day have been suggested for PTU, but are of relatively little use in practice. Table 14-15. Treatment guidelines for Graves' disease during pregnancy Monitor pulse, weight gain, thyroid size, serum free T4 and T3, and TSH every 2-4 1. weeks, and titrate ATD as necessary. 2. PTU is usually preferred to MMI, but both types of ATD can be used. Use the lowest dosage of ATD that maintains the patient in a euthyroid or mildly 3. hyperthyroid state. The ATD dose can usually be adjusted downward after 1st trimester and often discontinued during last trimester. Do not attempt to normalize serum TSH. Serum TSH concentrations between 0.1 & 0.4 4. mU/L are generally appropriate, but lower levels are acceptable if the patient is clinically satisfactory. While as little as 100-200 mg PTU/day may affect fetal thyroid function, dosages as 5. high as 400 mg PTU (~30 mg MMI) have been used. Communicate regularly with obstetric care providers, especially with respect to fetal 6. pulse and growth in the 2nd half of gestation. Consider thyroidectomy if persistently high doses of ATD are required (PTU >600 mg/d 7. or MMI >40 mg/d), or if the patient is not compliant or cannot tolerate the administration of ATD. Beta-adrenergic blocking agents and low doses of iodine may be used peri-operatively 8. to control hyperthyroidism. 9. ATD will often need to be reinstituted or increased after delivery. 2. Beta-adrenergic blocking agents Propranolol may be used transiently to control symptoms of acute hyperthyroid disease and for pre-operative preparation, and there are no significant teratogenic effects of propranolol reported in humans or animals 336. If a patient requires long-term propranolol
  • 57. administration, careful monitoring of fetal growth is advised, because of a possible association with intrauterine growth restriction 337. 3. Iodides Chronic use of iodide during pregnancy has been associated with neonatal goiter and hypothyroidism, sometimes resulting in asphyxiation because of tracheal obstruction 329, 338. One study investigating the use of potassium iodide (6-40 mg/d), administered to selected hyperthyroid pregnant patients, showed improved maternal function with a normal neonatal outcome 339. Because the experience with iodides is limited, iodide should not be used as a first line therapy for GD during pregnancy, but can be used temporarily in preparation for thyroidectomy. 4. Radioactive iodine administration Radioactive iodine administration is contraindicated during pregnancy. In case of inadvertent radioiodine administration, the fetus is exposed to radiation from mother’s blood (approximately 0.5-1.0 Rad per milli-Ci administered). Since fetal thyroid uptake of radioiodine commences after the 12th week, exposure to maternal radioiodine prior to this time is not associated with fetal thyroid dysfunction 340. However, treatment with radioiodine after 12 weeks leads to significant radiation effects on the fetal thyroid. Multiple incidents of inadvertent exposure to radioiodine have been reported, causing fetal thyroid destruction, in utero hypothyroidism, and subsequent neural damage 341, 342. 5. Surgery Thyroidectomy for Graves’ disease during pregnancy should be reserved as a second line of treatment in specific situations such as: a) persistent high ATD doses required to control maternal thyrotoxicosis; b) patients who present serious side effects to ATD (allergy, intolerance, etc.); c) patients who are non compliant; and finally d) rare cases with upper respiratory compressive symptoms due to goiter size. Thyrotoxic pregnant women should be prepared for surgery by using beta-blocking agents and a 10-14 days course of super- saturated potassium iodide solution (50-100 mg/d) in order to reduce vascularity of the thyroid gland. Surgery in pregnancy is deemed safest if it can be undertaken in the second trimester when organogenesis is complete, the fetus at minimal risks for teratogenic effects of medications, and the uterus relatively resistant to contraction-stimulating events 343. 6. Breastfeeding in mothers with treated Graves’ disease The question of the safety of lactation during ATD therapy arises frequently 326. Historically, women have been advised against breastfeeding when receiving ATD because of the presumption that ATD was present in breast milk in concentrations sufficient to affect infant’s thyroid function. Both PTU and MMI are secreted in human milk, although PTU less so because of more extensive binding to albumin 344-347. In one study evaluating the effects of CMI (15 mg/d) or PTU (150 mg/d) on infants of nursing mothers, there was no evidence of neonatal hypothyroidism in the first weeks of life 348. In another study, serum MMI levels were measured in breastfed infants of thyrotoxic mothers receiving MMI (20-30 mg/d): two hours after MMI ingestion, serum MMI levels in the babies were extremely low, far below the therapeutic range 349. Thus, with both PTU and MMI, only limited quantities of the drugs are concentrated into milk. As long as the doses of MMI or PTU can be kept moderate (MMI: <20 mg/d; PTU: <250-300 mg/d), the risk for the infant is practically negligible and there is no evidence-based argument to advise mothers against nursing when they take ATD 304, 326, 350. The drug should be taken by the mother after a feeding and it is prudent to monitor the infant's thyroid function periodically during the time of ATD administration, although a recent study showed reassuringly that thyroid function was not affected in breastfed infants, even when ATD induced maternal hypothyroidism 351. There is also a possibility that allergic reactions associated with ATD (agranulocytosis or rash) may occur in the infant. While these side effects are rare, they should be kept in mind when evaluating a febrile infant or
  • 58. presence of rash. In summary, within the limitations outlined above, the use of ATD in lactating mothers does not pose a risk to the neonate and appears to be safe. Fetal & neonatal adverse effects of maternal hyperthyroidism 1. Fetal thyroid function TRAb may have stimulatory or inhibiting effects on the thyroid gland 352. Thus, depending upon the balance between these opposite effects, TRAb production in pregnant women with GD may stimulate or inhibit the fetal thyroid gland. Inhibitory TRAb production has been shown to cause hypothyroidism transiently in neonates born to mothers with GD 156, 353. When maternal TRAb production with stimulating activity is elevated and antibody titers do not substantially decrease in the second part of gestation, fetal (and neonatal) hyperthyroidism constitutes a real risk 316-318, 354. One to 5% of neonates of mothers with GD have hyperthyroidism (neonatal GD) due to the trans-placental passage of stimulating maternal TRAb. The overall incidence is low because of the balance between stimulatory and inhibitory antibodies, and also maternal treatment with ATD 316. The incidence of neonatal GD is not directly related to maternal thyroid function. Risk factors for neonatal thyroid dysfunction include history of a previously affected baby, prior radioiodine ablative treatment, and elevated TRAb titers at delivery 315, 316, 318, 355. In the study by Mitsuda et al. for instance, the incidence of neonatal thyroid dysfunction was 67% when maternal TRAb was >130% and as high as 83% when TRAb was >150%, compared with only 11% when TRAb was <130% of normal (normal TRAb in this study was <115%) 315. The risk of fetal hyperthyroidism can be assessed by fetal ultrasonographic data, showing the presence of fetal goiter, tachycardia, growth retardation, increased fetal motility, and accelerated bone maturation 305, 356. When fetal hyperthyroidism is suspected in utero, it is reasonable to initiate ATD treatment with PTU (200-400 mg/d) or MMI (20 mg/day) combined with thyroxine administration, when required, to maintain maternal euthyroidism. ATD treatment may thus be given based on a presumptive diagnosis, but the definitive diagnosis of fetal hyperthyroidism may require umbilical cord blood sampling for fetal thyroid hormone determination. This procedure carries, however, a significant risk for the fetus (complications and/or fetal loss in 1% of cases) 357-361. Administration of ATD to treat maternal GD may induce fetal hypothyroidism that should be avoided in view of its potential deleterious consequences for the neuro-psychointellectual development. In clinical practice, the best way to avoid fetal hypothyroidism is to keep maternal circulating thyroid hormone levels in the upper quartile of the normality range 335, 362, 363. As alluded to above already, radioactive iodine has unintentionally been administered (in exceptional cases) to GD women who were unaware that they were pregnant and who decided, nevertheless, to maintain the pregnancy. In one such recently published case report, the authors showed the advantage – despite the obvious risks associated therewith – of performing cordocentesis to predict the fetal outcome 364. Subclinical hyperthyroidism (defined as a serum TSH below normal limits with free T4 and total T4 levels in the normal pregnancy range, and unaccompanied by specific clinical evidence of hyperthyroidism) can be observed in maternal GD, although it is more often found in association with gestational transient thyrotoxicosis. Treatment of maternal subclinical hyperthyroidism has not been found to improve pregnancy outcome and may risk unnecessary exposure of the fetus to antithyroid drugs 357, 363, 365-367.
  • 59. 2. Fetal goiter in mothers with Graves’ disease The treatment of maternal hyperthyroidism may be associated with the presence of fetal goiter, thus raising clinical concern with regard to its etiology and management. Fetal goiter may result directly from the placental transfer of thyroid growth-stimulating effects of maternal TRAb, as well as from ATD’s inhibitory effect on the fetal gland inducing fetal hypothyroidism 368-373. This complex – but highly important – topic was recently revisited. Gallagher et al. showed that the spectrum of neonatal thyroid dysfunction in pregnant women with GD receiving ATD ranged from frank hypothyroidism (secondary to the exposure to PTU and maternal blocking TRAb) to neonatal Graves’ thyrotoxicosis (secondary to exposure to maternal stimulating TRAb) and that the prenatal diagnosis remained often extremely complex 374. The group of Michel Polak in Paris reported their experience on a large group of mothers with past or present GD, who had been investigated using clinical evaluation, TRAb measurements, as well as ultrasound evaluation of the fetal thyroid and bone age 373, 375. Details of the main results are shown on Figure 14-16 (upper panel). In 31 pregnancies with no detectable TRAb and mothers without ATD treatment, all infants were normal at birth. In the remaining 41 pregnancies, 30 women had positive TRAb and/or a treatment with ATD: fetal thyroid ultrasound was normal (32 wks gestation) and there was almost no evidence of fetal thyroid dysfunction. Finally, 11 fetuses were found to have a goiter, of which 7 were hypothyroid and 4 hyperthyroid. Figure 14-16 (lower panel) outlines the main risk factors for fetal hyper- and hypothyroidism when a fetal goiter is found in women with ATD treated GD. Based on their observations, the authors recommended TRAb measurement in women with current or past GD at the beginning of pregnancy, and close observation of those pregnancies with elevated TRAb or ATD treatment by performing monthly fetal ultrasonography after 20 weeks of gestation. Fetal/Neonatal thyroid dysfunction in newborns from mothers with GD 72 mothers with present or past Graves’ disease  31 mothers : no ATD and negative TSHR-Ab  all newborns were normal  41 mothers : with ATD and/or positive TSHR-Ab  30/41 newborns : normal fetal US thyroid normal TFTs (except for 1)  11/41 newborns : fetal goiter at US examination and abnormal TFTs  7 hypothyroid  4 hyperthyroid (hypo : low TRAb ; high ATD) (hyper : high TRAb ; low ATD)
  • 60. Fetal Goiter Fetal HYPO: Fetal HYPER: Risk factors Risk factors • Poorly controlled maternal • Mother with GD treated hyperthyroidism with ATD; serum free T4 • Elevated TSHR-Ab titers in normal lab reference range (mother under l-T4 after RI* • Low (or absent) TSHR-Ab or surgery) • Blocking-type TSHR-Ab (rare) • Fetal tachycardia • Delayed bone age • Advanced bone age Figure 16: Upper panel: data on 72 mothers with Graves’ disease (adapted from the study of Luton et al., Ref 373). Lower panel: main risk factors for fetal hyperthyroidism and hypothyroidism associated with fetal goiter in mothers with Graves’ disease (adapted from Chan & Mandel, Ref 376). 3. Teratogenicity of maternal treatment with ATD Both thyrotoxicosis by itself and the administration of ATD to the expecting mother may raise concern with regard to potential teratogenicity associated with the disease and the medications. To date, it remains uncertain whether untreated GD is associated with a higher frequency of congenital abnormalities 315, 326, 376. Concerning the antithyroid drugs, there have been reports of two distinct teratogenic patterns associated with the administration of MMI, namely aplasia cutis congenita and choanal/esophageal atresia, although data supporting these associations remain somewhat controversial 377-380. Aplasia cutis is the absence of skin and accessory structures over the scalp and has, so far, not been reported (or only exceptionally) in mothers receiving PTU. The so-called ‘methimazole embryopathy’ includes congenital abnormalities such as choanal and/or esophageal atresia, minor dysmorphic features and developmental delay 305. After reviewing the evidence linking ATD treatment with such fetal abnormalities, one comes to the conclusion that the prevalence of these malformations remains extremely rare: 2/241 MMI-exposed infants, for instance, in the series reported by Di Gianantonio 381. A recent case report from Japan illustrates the complexities in our understanding of fetal abnormalities found in association with MMI administration during pregnancy. The authors reported the case of a monozygotic twin with aplasia cutis after in utero exposure to MMI, namely that of a girl born at 36 weeks gestation. Her mother had received MMI: 15-30 mg daily, from the 11th to 17th week of pregnancy. However and to everybody’s surprise, the second child of these monozygotic twins did not have aplasia cutis 382. In view of the potential danger – both for mother and offspring – of not treating active GD during pregnancy, the concern posed by these rare congenital abnormalities would not, in our opinion, justify withholding ATD administration. However, despite the fact that the link between severe congenital defects and MMI exposure during pregnancy has not been
  • 61. formally established, it appears prudent to avoid the use of MMI during embryogenesis and to prefer the use of PTU, when available. 4. Neonatal thyrotoxicosis Undetected fetal thyrotoxicosis may be followed by thyrotoxicosis at birth. Neonatal thyrotoxicosis is considered to be uncommon, occurring in ~1% of pregnancies in patients with Graves’ disease in North America 5, 156. In a recent reevaluation of this topic, it was suggested that the actual prevalence of neonatal thyrotoxicosis may be significantly higher, in the order perhaps of 2-10% 304, 316. Risks appear highest in the offspring of women with not-well-controlled GD, as well as in women with the highest TRAb titers. Mothers with a prior history of bearing infants with neonatal GD are also at high risk of repeated episodes 156, 159. Neonatal GD is usually diagnosed at or shortly following birth, after maternal ATD has been cleared from neonatal serum and thyroid gland. Signs of neonatal thyrotoxicosis include congestive heart failure, goiter, proptosis, jaundice, hyperirritability, failure to thrive, and tachycardia. Once considered, the diagnosis should be readily confirmed. Cord serum free T4 and TSH determinations should be performed in all deliveries of mothers with a history of GD. Treatment should be initiated out in conjunction with the neonatalogist, and may include iodide, ATD, glucocorticoids, digoxin, and beta-adrenergic blocking agents, depending on the cardiovascular status. Neonatal hyperthyroidism may have a delayed onset in some infants, particularly those in whom both anti-TSH receptor blocking and stimulating antibodies coexist. Thus, the pediatrician should be alerted to measure serum free T4 if symptoms suggesting thyrotoxicosis appear during the first 6-8 weeks of life, even if cord serum results were normal, and especially when cord serum TSH was suppressed 326, 356, 360, 362, 383-385. 5. Neonatal central hypothyroidism There have been several reports of infants who presented central congenital hypothyroidism, being born to mothers with uncontrolled hyperthyroidism due to GD 304, 386, 387. The explanation is based on the notion that high maternal serum T4 levels, during a prolonged period of time, crossed the placental barrier and suppressed fetal TSH by pituitary feedback. In most cases, the diagnosis was made at birth or shortly thereafter, on the basis of a low neonatal serum total T4 contrasting with an inappropriately low serum TSH. In the majority of these infants, there was a return to euthyroidism within a few weeks or months. However, a recent publication has suggested that in children born to mothers with inadequately treated GD during pregnancy, there may also be a risk of thyroid ‘disintegration’ (i.e. abnormal ultrasound patterns found during childhood), possibly as the result of prolonged central hypothyroidism 388. Hyperthyroidism in the early postpartum period Two major forms of hyperthyroidism can be observed in the early postpartum period. They are due to GD or hyperthyroidism related to postpartum thyroid dysfunction (PPTD). Both entities have in common that serum TSH is suppressed and free T3 & T4 levels elevated; both diseases can present shortly after delivery and are associated with enlargement of the thyroid gland and presence of TPO-Ab. Presence of exophthalmos, a bruit, and positive TRAb are characteristic of GD. However, infrequently, women with PPTD may also be TRAb-positive. From an epidemiological standpoint, the most likely etiology of postpartum hyperthyroidism is PPTD, as its prevalence is much greater than that of GD (4.1 vs. 0.2%) 152, 305, 389-391. For the differential diagnosis between these entities, a thyroid scan can be required. Women with PPTD have a marked diminution of tracer uptake by the thyroid, contrasting with the increased tracer uptake that is typical of GD. In women with very mild hyperthyroidism during postpartum, it is reasonable to repeat thyroid function tests 4 to 6 weeks later, prior to scanning. In this condition, the gradual resolution of hyperthyroidism is
  • 62. consistent with a transient hyperthyroid phase associated with PPTD, and would therefore obviate the need for thyroid scanning 392. When patients present clinically overt hyperthyroidism related to PPTD, the diagnosis can perhaps be predicted based on the titers of thyroid antibodies during early pregnancy and an abnormal thyroid echogenic pattern at ultrasound examination during early postpartum 393, 394. Concerning GD, it is important to note that the disease often recurs during postpartum and also that a clinically significant number of women develop GD de novo after childbirth 395-397. Recommendations and ‘take home’ messages The two most common causes of hyperthyroidism during pregnancy are Graves' disease (GD) and gestational transient thyrotoxicosis (GTT). If a subnormal serum TSH is detected during gestation, hyperthyroidism must be first distinguished from normal gravid physiological changes and hyperemesis gravidarum. Differentiation of GD from non autoimmune GTT is supported by evidence of typical goiter and autoimmunity, specifically presence of anti-TSH receptor antibodies (TRAb). For the treatment of active GD in pregnancy, antithyroid drug (ATD) therapy should be initiated (or adjusted) with the aim to control maternal hyperthyroidism. Maternal free T4 levels should be maintained in the upper non pregnant reference range. Both PTU and MMI can be used during pregnancy, but it is recommended to use PTU as a first line drug, if available. Thyrotoxicosis by itself and ATD administration may raise concern related to potential teratogenicity of the disease or/and the drug (aplasia cutis; choanal/esophageal atresia); such congenital defects are rare and do not justify withholding ATD administration. An important concept is that maternal and fetal outcome is directly related to adequate control of thyrotoxicosis. Obstetrical repercussions of poorly controlled thyro-toxicosis include risks of miscarriage, gestational hypertension, fetal malformation, premature delivery and low birth weight. Maternal GD can affect the fetus in several ways. TRAb freely cross the placenta to stimulate the fetal thyroid. These antibodies should be measured before pregnancy or by the end of the second trimester in mothers with current GD, a history of GD and prior curative treatment (by radioiodine or thyroidectomy), or a previous neonate with GD at birth. Women with negative TRAb and who do not require ATD have a very low risk of fetal or neonatal thyroid dysfunction. In women with positive TRAb, fetal & neonatal thyrotoxicosis constitutes a real risk when maternal TRAb titers have not substantially decreased during the second half of gestation. In women with elevated TRAb or receiving ATD, fetal ultrasound should be performed to search for evidence of fetal thyroid dysfunction. Umbilical blood sampling should be considered only if the diagnosis of fetal thyroid disease is not reasonably certain from the clinical data and if the information gained would change the treatment. All newborns of mothers with GD should be evaluated for thyroid dysfunction and treated when necessary. In breast-feeding mothers who take ATD, there is no evidence-based argument to advise them against nursing, as long as the doses of ATD can be kept moderate.
  • 63. Gestational non autoimmune hyperthyroidism Thyrotoxicosis and hCG The thyroid stimulating activity of human chorionic gonadotropin (hCG), its stimulatory effects on maternal thyroid function and its causal relation with hyperemesis gravidarum (HG) have already been discussed in the first section of this chapter (see ‘Effects of hCG on thyroid function’ and ‘Hyperemesis Gravidarum’). Non autoimmune gestational hyperthyroidism or gestational transient thyrotoxicosis “GTT” is characterized by elevated serum free T4 and T3 levels, suppressed TSH, variable clinical evidence of hyperthyroidism, usually minimal thyroid enlargement, and absence of thyroid auto-antibodies. The syndrome occurs transiently near the end of the 1st trimester of gestation, usually in hitherto healthy women who have otherwise a normal pregnancy, and it is frequently associated with excessive vomiting 6, 14, 39, 41, 42, 350, 398. GTT differs fundamentally from GD in that it occurs in women without past history of GD and absence of detectable anti-TSH receptor antibodies (TRAb). GTT is not always clinically apparent, due to its transient nature. Its etiology is related to the thyrotropic stimulation of the maternal thyroid gland associated with elevated hCG levels (see Figure 14-17). The prevalence of GTT is highly variable in populations of normal pregnancies. Prospective studies carried out in Europe have indicated that the prevalence may reach 2-3% of unselected pregnancies (that is 10-fold more prevalent than GD) 208. In other regions of the world, the prevalence of GTT appears to be as low as 0.3% (Japan) or as high as 11% (Hong Kong) 399, 400. Figure 17: Human CG levels measured at different time points during gestation in women with a diagnosis of GTT. The curve flanked by the dashed lines in the lower part of the graph
  • 64. represents the mean hCG levels (with 95% confidence intervals) determined in a cohort of normal pregnancies, showing the classical hCG peak near the end of the first trimester. The individual points show serum hCG levels in fifteen women with GTT, at the time of their recall, i.e. 3-6 weeks after initial screening for thyroid function. Initial diagnosis was based on suppressed serum TSH with elevated free T4 concentrations. All women clearly had abnormally elevated hCG values, even when the measurements took place several weeks after peak hCG. In a few cases, hCG was measured again during follow-up in the 2nd trimester and the results showed sustained abnormally elevated serum hCG levels. (from Glinoer, Ref 32) Owing to the transient nature of the syndrome, clinical manifestations of hyperthyroidism are not always apparent or routinely detected. When women followed in our institution were specifically questioned about possible symptoms compatible with thyrotoxicosis, we found weight loss (or absence of weight increase), tachycardia and unexplained fatigue in one half of the women with GTT. Hyperemesis gravidarum was frequently associated with the most severe cases, and in a few women symptoms were sufficiently alarming to justify hospitalization for treatment. In cases followed until parturition, GTT was always transient; elevated serum free T4 values reverted gradually to normal in parallel with the decrease in hCG concentrations. Serum TSH often remained partially (or totally) suppressed for several weeks after free T4 reverted to normal, i.e. until after mid-gestation 401, 402. GTT was not associated with a less favorable outcome of pregnancy. It should also be noted that GTT may occur, by coincidence, in women with preexisting thyroid disorders, such as glandular autonomy, autoimmune thyroiditis or GD, and even in women with genetic resistance to thyroid hormone 403. The association of GTT with an underlying thyroid abnormality often leads to more severe presentations of thyrotoxicosis. The stimulatory effect of hCG may also help explain the exacerbation of thyrotoxicosis due to GD, that is sometimes encountered during the 1st trimester 324. Finally, when women with GTT are followed in subsequent pregnancies, the syndrome has a characteristic tendency to relapse. Twin pregnancy & gestational transient thyrotoxicosis (GTT) Normal women develop GTT essentially when they have abnormally elevated peak hCG levels and when these very high hCG values are sustained during an unusually prolonged period 404. Twin pregnancy is a naturally occurring clinical condition associated with sustained and high hCG concentrations (see Figure 14-18). Peak hCG values were shown to be significantly higher (almost double) and of a much longer duration in women with a twin pregnancy. While peak hCG values lasted only for a few days in singleton pregnancy, peak hCG levels (>100,000 UI/L) lasted for up to six weeks in twin pregnancies. Twin pregnancy was associated with a more profound and 3-fold more frequent suppression of serum TSH values. Also, while serum free T4 levels remained unaltered in singleton pregnancy, they often rose transiently above normal in twin pregnancy. Symptoms related to thyrotoxicosis were usually mild or absent, except for more intense vomiting which was more frequently noted (obstetricians often observe increased nausea and vomiting in women with a twin pregnancy).
  • 65. TWIN Twin versus Single Pregnancies SINGLE -3) Intact hCG (IU x 10 FT4 (pmol/L) TSH (mIU/L) 200 20 * 18 3.0 150 16 * 14 2.0 100 12 * 10 1.0 50 8 0.1 0 6 10 20 30 10 20 30 10 20 30 Weeks of gestation Figure 18: Profiles of changes in hetero-dimeric intact hCG, serum free T4 and serum TSH, comparing women with singleton (pale blue) and thirteen women with a twin pregnancy (pink color). Each point corresponds to the mean (± 1 sd) of individual serum samples measured at each gestational age (from Grün et al., Ref 404). Treatment No trial has been carried out to delineate precisely which patients with GTT require a specific treatment. In most cases, no specific treatment is required and symptoms can be relieved by administration of beta-adrenergic blocking agents for a short period, while waiting for the spontaneous recovery of elevated thyroid hormones to occur. In patients with a severe clinical presentation (clear symptomatic hyperthyroidism), some – but not all – authors suggest starting treatment with PTU, usually for a few weeks only. Therapy is often discontinued by mid-gestation. As already indicated in the section on treatment for GD, the treatment of subclinical hyperthyroidism has not been found to improve pregnancy outcome and may risk unnecessary exposure of the fetus to ATD 357, 363, 365-367. Pathogenic mechanisms in GTT The precise pathogenic mechanisms underlying GTT are still not fully understood but the etiology of the syndrome is felt to be hCG itself or derivatives of hCG 14. Based on the example of GTT associated with twin pregnancy, a direct quantitative effect of elevated hCG concentrations to stimulate the thyroid gland is probably sufficient to explain hyperthyroidism in most pregnant women, provided that hCG remains above 75,000-100,000 UI/L for a sufficient period of time. Thus, GTT is directly related to both the amplitude and duration of
  • 66. peak hCG values 404. Human CG acts as a weak TSH agonist to increase cAMP production, iodide transport and cell growth in thyrocytes 42, 49, 50. It remains possible that abnormal h CG molecular variants, with a prolonged half life, are produced in these situations explaining sustained prolonged high circulating hCG levels 30. It has also been hypothesized that a dysregulation of beta-hCG production may transiently take place in these women 24. Finally, hCG molecular variants with a more potent thyrotropic activity have been detected, although these variants appear to be more specifically found in women with hydatidiform mole or choriocarcinoma 405-407. Whatever the final explanation, hCG effects to stimulate the thyroid can be best explained by the marked homology between hCG and TSH molecules, as well as between LH/CG and TSH receptors 408, 409. Gestational non autoimmune hyperthyroidism can be considered an example of an endocrine ‘spill-over’ syndrome, a concept based on molecular mimicry between hormone ligands and their receptors 14, 50, 300, 405. TSH receptor mutations hypersensitive to hCG An interesting – although unresolved – question is whether the thyrocyte is a passive bystander of abnormal thyrotropic activity of hCG in GTT, or whether the thyrocyte itself, through variable degrees of sensitivity of the TSH receptor, may play an active role in its responsiveness to hCG’s stimulatory effect. A woman with recurrent gestational hyperthyroidism was reported by Rodien et al. in 1998 410. After two miscarriages, she presented hyperemesis with overt hyperthyroidism early in pregnancy, requiring treatment with PTU. During her next pregnancy, she experienced a relapse of the same situation. The patient’s mother had also been diagnosed with hyperthyroidism during her 2nd and 3rd gestations, mistakingly considered to be GD. Study of the TSH receptor of this patient disclosed a single mutation in the extracellular domain of the TSH receptor (K183R), rendering the mutant receptor highly sensitive to hCG, and accounting for recurrent thyrotoxicosis during pregnancies in the presence of normal hCG levels. Thus so far, only one fascinating example has been reported of a substantially increased sensitivity of the TSH receptor to the stimulatory effect of hCG in humans. This unique finding raises the possibility that some women who develop GTT may have an abnormality at the level of the thyroid follicular cell (see Figure 14-19). In further studies of structure-phenotype relationship at the level of the TSH receptor, the group of Gilbert Vassart carried out site-directed mutagenesis, substituting lysine 183 in the ecto-domain of the TSH receptor by a variety of amino acids expressing different physicochemical properties 16, 411. Somewhat unexpectedly, all mutant TSH receptors displayed a widening of their specificity toward hCG stimulation. Modeling of the mutated receptors indicated that the increased gain of sensitivity might result from the release of a nearby glutamate residue (in position E157) from a salt bridge formed with K183. As of now, this situation remains exceptional since most patients with gestational non autoimmune transient hyperthyroidism do not seem to be familial and almost invariably have hCG levels >100.000 UI/L 412.
  • 67. Natural Gain of Function. A MUTANT TSH RECEPTOR, HYPERSENSITIVE TO hCG RESPONSIBLE FOR FAMILIAL GESTATIONAL THYROTOXICOSIS M R P A D L L Q L V L L L D L P R D L G G M G CS S P P C E C I:1 H Q A H S P I T R L H T E I L K L T Q T S P P L S P Ι R Q Ι D K C T V R F D E E F S N L P N I S R T Y V S I D L T L Q Q L E S H S F Y N L S K V T H Ι E Ι R N T RN L T Y Ι I F F I D T S Y V K T L D P F M K L G T N F Ι G L F K L L P L E K L A D P D II:1 Lys183Arg L E I K D N P Y M T S I P V N A F Q G L C N E T L T L K L Y N N G F T S V Q G Y A F N G T Q S V D L L S P G S Y V GG F A D K D Ι V T L Y K NK N L T V A D L K T V S T A L P S K G L E H L K E L I A R N T W T L K K L P L S L S F L H L T R A D L S Y C 80 Q H L P S N L A N V S K R Q R L S Q M S S E N C M L S E L Ι G R Ι K K Q N K F A C E K183R Y 70 E E N L G D S I V G Y K E K S K F Q D T HN N A H Y Y F F E E Q E D E Ι Ι G cAMP (picomoles/ dish) F TSHr wt Q G 60 Mock-transfected cells E C P N F E D S K P T C V M D E S D G C Ι T Y D Y H S D F A Q L T E E Q P N K L E D N H I Y L P 50 M G Y Y E S W Q V M D T K H T K E L I V F T G A T S 40 R L I V Y L D P G C N T S S P L A L N S K I W V S V A A T G I V Y I A A I S L F V I L L L L S L L L F L P L V Y A F L F V L F 30 L L A V F N G M Y G F C D M E L A L CC V F L N T I V N I S CM I A P A F A D F T W L L V T G L Y F V G F L T L I C I T V I M A CF A I L I V 20 S H Y F R P E R L A C H R V K I T K M A A F K V W L Y Q L N Y R I R 10 A T I I K R K T V R D V F F D N I A M R L P L Q 0 G L Y N P S K F -1 0 1 2 3 E D M N H L G Q R M D H T V K Q V Q I D T S N K P P V R Q G R Y A Q A Q R K C I G Log hCG concentration (U/ml) V YE L I E N S H L T P K K Q G Q I S E E Y M Q T V L Figure 19: TSH receptor mutation, with a Lysine to Arginine mutation in position 183 of the ecto-doamin. The graph on the left shows that the mutation confers high sensitivity to hCG (red curve), compared with wild type TSH receptor (blue curve). The family tree (upper right) shows the pedigree of the patient. (from Rodien & Vassart, Refs 410-412). Hyperemesis Gravidarum and gestational hyperthyroidism As alluded to in the first sections of this Chapter, GTT is often associated with nausea (morning sickness), increased vomiting and hyperemesis gravidarum, a severe condition requiring hospitalization and drastic treatment. Several studies have established a correlation between the severity of vomiting and abnormal thyroid function. Thirty to sixty percent of patients with hyperemesis gravidarum have elevations of free thyroid hormone concentrations, along with a suppressed TSH, and in the absence of any evidence of Graves’ disease 38, 42, 413. A common observation among obstetricians is also that women with a twin pregnancy often experience more severe vomiting during early gestation. Increased vomiting is not customary associated with hyperthyroidism due to GD in pregnancy. Thus, hyperemesis appears to be associated mainly with hCG-induced thyrotoxicosis, although evidently all women who vomit during early pregnancy do not have disturbances of thyroid function. One likely explanation is that elevated and sustained hCG levels in the circulation promote estradiol production in these women; the combination of elevated hCG, estradiol and free T4 concentrations then transiently promotes emesis near the period of peak hCG, by some yet not fully understood mechanism 14, 42, 50, 400, 405. A recent matched-paired study in fifty-eight pregnant Chinese women showed that women with hyperemesis gravidarum were younger and had higher serum free T3 and T4 levels, as well as higher s -hCG concentrations 414. In this study, logistic regression analysis of the data showed that the principal determinant for having hyperemesis was the high free T4, and not the high hCG levels. Thus, these results reinforce the concept that hCG is not independently
  • 68. involved in women with hyperemesis gravidarum, but rather indirectly by stimulating the thyroid to induce gestational hyperthyroidism. Recently, the first case report was published of a woman with a partial molar pregnancy who presented hyperthyroidism leading to a thyrotoxic storm 415. This case presented two interesting clinical features. The first feature was that the mole was ‘partial’, hence allowing a viable pregnancy to proceed up to 13-14 weeks, but also severe thyrotoxicosis to develop. The second feature was that there was an unusually long time lag between the different clinical events. The diagnosis of hyperemesis gravidarum had been made four weeks before admission and hyperthyroidism was already present at that time. Thereafter, the clinical situation continued to deteriorate rapidly, eventually leading to the classical picture of a thyrotoxic storm, rapidly cured by the evacuation of the molar pregnancy. Recommendations and ‘take home’ messages Gestational hyperthyroidism or transient thyrotoxicosis (GTT) is defined as a transient increase in thyroid hormone production, of non-autoimmune origin, leading to variable degrees of hyperthyroidism and frequently associated with hyperemesis. The prevalence of the syndrome is 2-3 % of all pregnancies. Thyroid function tests should be measured in all patients with hyperemesis gravidarum. A quantitative direct effect of elevated hCG to stimulate the thyroid gland explains most cases with GTT, when hCG remains above 100,000 UI/L for a prolonged period of time. GTT is directly related to the amplitude and duration of peak hCG values and can therefore be considered as an example of endocrine spill-over syndromes, a concept based on molecular mimicry between hormone ligands (TSH & hCG) and their respective receptors. Owing to the transient nature of GTT, clinical hyperthyroidism is not always apparent, and symptoms suggesting thyrotoxicosis are found in ~50% of women with GTT. In most cases, no specific treatment is required; symptoms can be relieved by beta- adrenergic blocking agents. In rare cases, severe clinical presentation may require treatment with PTU as long as clinically necessary, usually less than two months. Concerning emesis, the most likely explanation is that elevated hCG levels promote estradiol production and that the combination of high hCG, estradiol and free T4 concentrations promotes emesis near the period of peak hCG.
  • 69. NODULAR THYROID DISEASE Thyroid nodule growth during pregnancy Thyroid nodules are common in young women and medical care provided during pregnancy may present the first opportunity for a thyroid nodule to be clinically recognized 416, 417. A few studies have evaluated the incidence of thyroid nodules and nodule changes associated with pregnancy, in areas with borderline iodine sufficiency or mild iodine deficiency. In a prospective study performed in Brussels, thyroid nodules were diagnosed by ultrasound at initial presentation during early gestation in 3% of a cohort of normal pregnancies 176. Repeat ultrasound performed within a week after delivery revealed a 60% increase in the size of the known nodules and detection of new nodules in 20% of these women. In another study in Northern Germany, the presence of thyroid nodules was shown to be significantly greater in women with prior pregnancies compared to nulliparous women (25% versus 9%). Furthermore, women with three or more pregnancies had a higher percentage of thyroid nodules, compared with women who had one or two prior pregnancies (34% versus 21%) 418. Finally in a study from Southern China, women were evaluated in the 3 trimesters of pregnancy and early postpartum 419. Thyroid nodules were detected in 15% of women in 1st trimester, and there was a significant increase in their volume, as well as new nodule formation during pregnancy. Thus, in areas with mild iodine insufficiency, pre-existing nodules are prone to increase in size during pregnancy. Furthermore during the course of pregnancy, new nodules will be detected in approximately 15% of women. Unfortunately, data on nodule growth and formation in iodine- sufficient areas are not available. Diagnostic evaluation of a thyroid nodule in pregnancy Diagnostic evaluation of thyroid nodules discovered during pregnancy should be similar to that of non-pregnant patients, but the ongoing pregnancy raises an additional concern regarding timing of surgical management 420-424. The diagnosis and decision-making for overall management of a nodule diagnosed in pregnancy relies primarily on the results of thyroid ultrasound and fine needle aspiration biopsy (FNAB). Despite the fact that a minority of nodules are potentially malignant, the fear of cancer may be accentuated in pregnant women. Therefore, diagnostic investigation using FNAB is recommended in most pregnant women. A number of studies have suggested that a delay in the work-up of a nodule until after delivery causes no change in final prognosis as compared with surgical resection of a malignant lesion in the second trimester 422, 425. Knowing the diagnosis via FNAB cytology is, however, often helpful to the mother in planning the postpartum period, including decisions regarding breast-feeding and the potential need for adjunctive therapy with radioiodine after surgical removal of a cancer. Furthermore, a delay in surgical treatment of thyroid cancer beyond a one-year period is not recommended because of increased likelihood of cancer complications 421. Thyroid ultrasonography is useful to characterize the dominant lesion (solid versus cystic), identify other non-palpable nodules within a nodular goiter, monitor nodule growth, etc. Thyroid ultrasound is also a useful adjunct to guiding the FNAB procedure. FNAB is safe and diagnostically reliable and should be routinely performed when any single or dominant thyroid nodule greater than 1 cm has been discovered 1, 417. In the particular context of a nodule identified during pregnancy, and because of the potential therapeutic implications, it is highly important that FNAB be carried out and analyzed by experienced teams.
  • 70. Management Subsequent management depends on results of FNAB cytology. Most nodular lesions are cytologically benign and do not require surgery. If cytology is suspicious or positive for thyroid cancer, treatment decision-making must take into account the gestational age, the apparent tumor stage and the personal inclination of the patient. If FNAB cytology is highly suggestive of papillary, follicular, or medullary carcinoma, surgery is offered in the 2nd trimester, before fetal viability 426. Surgery for papillary cancer may be postponed until after delivery because there is no evidence that pregnancy worsens the prognosis or that waiting until postpartum alters the long term prognosis of a well-differentiated thyroid cancer 420, 422, 425, 427. When cytology is highly suggestive of a follicular neoplasm, the risk of malignancy is 10%-15% and thyroid surgery can be delayed, if preferred, until a short time after delivery. In patients who need to be reassured or when there is significant growth of the nodule before mid-gestation, surgery is a valid option and should be carried out during the second trimester. For follicular neoplasms with Hurthle cell features (i.e. oncocytes), the patient should be encouraged to have surgery during pregnancy, given the more aggressive behavior of Hurthle cell carcinoma 428. Finally, when a nodule is discovered in the third trimester, further work-up and treatment can be delayed until after delivery 429, 430. Overall, most experts in the field agree that pregnancy does not worsen the prognosis of differentiated thyroid carcinoma and there is, therefore, no justification to recommend interrupting the pregnancy. In a recent study, the long-term outcome of a large grop of women diagnosed with thyroid cancer was evaluated 431. The authors observed no significant difference in the outcome, compared with an age-matched non pregnant cohort. Furthermore, there was no adverse effect of surgery performed during pregnancy on the outcome of pregnancy. One frequently asked question concerns the risk of a pregnancy in thyroid cancer survivors. Recent data have indicated that pregnancy is unlikely to cause clinically significant disease recurrence in women treated previously for differentiated thyroid cancer who are considered free of residual disease 432. However occasionally, pregnancy can be associated with progression of known metastatic lesions 433. Recommendations and ‘take home’ messages Fine needle aspiration (FNA) cytology should be performed for all thyroid nodules greater than 1 cm, discovered in pregnancy. Ultrasound guided FNA may have an advantage for minimizing inadequate sampling. When nodules are discovered in the 1st or early 2nd trimester to be malignant on cytological analysis or exhibit rapid growth, pregnancy should not be interrupted but surgery offered in the 2nd trimester, before fetal viability. Women with cytology indicative of papillary cancer or follicular neoplasm without evidence of advanced disease, and who prefer to wait until the postpartum period for definitive surgery, may be reassured that most well differentiated thyroid cancers are slow growing and that surgical treatment soon after delivery is unlikely to change prognosis. Thyroid hormone administration is justified to achieve a slightly suppressed (but detectable) serum TSH in pregnant women with an FNAB positive for or suspicious for cancer and who elect to delay surgical treatment until postpartum.
  • 71. SCREENING FOR THYROID DISORDERS ASSOCIATED WITH PREGNANCY Prerequisites for screening in primary prevention In primary prevention, screening is defined as testing for a disease when there are no signs or symptoms, with the aim of improving health outcomes by early diagnosis followed by treatment (when required) or monitoring. In order to justify systematic screening for primary prevention in medicine, a number of prerequisites has, ideally, to be met: Prevalence of disease must be high enough to justify screening. Laboratory techniques must be available to reliably detect disease, and these techniques must have high positive and negative predictive values. Screening procedures must be safe (i.e. with very low co-morbidity). Adequate medical intervention (such as medication) must be available, so that a given diagnosis can be followed by adapted therapy. Benefits of medical intervention should outweigh potential risks of secondary negative side effects of both screening and therapy. Evidence-based medicine should ideally have clearly established the usefulness of screening. This issue obviously also implies health policy and cost-benefit considerations, although the latter will always remain controversial since cost-benefit evaluations are highly variable from country to country and depend primarily upon applicable national social security systems and health insurance policies. Evidence-based medicine must show decreased morbidity and/or improved health status when treating conditions detected by screening procedures. When trying to assess whether such prerequisites have been met (completely or partially) for thyroid disorders associated with pregnancy, what can we conclude? Concerning the prevalence of thyroid disorders, many studies have shown that 5-15% of pregnant women have thyroid autoantibodies, 2-3% of them have undiagnosed hypothyroidism, and 0.3-0.5% undiagnosed hyperthyroidism 1, 212, 434. Based on our own pregnancy studies in Belgium, Figure 14-20 shows the different thyroid conditions that were observed in successive prospective cohort studies involving altogether ~2.400 women. The data indicate clearly that the overall prevalence of thyroid disorders associated with pregnancy is sufficiently high to warrant screening. With regard to the laboratory techniques (reliability & safety), the two main candidates for screening are serum TSH and detection of TPO-Ab. More complete testing should also include detection of Tg-Ab and serum free T4 measurement. Preliminary results from an ongoing prospective study in Wales, (the ‘CATS study’ or Controlled Antenatal Thyroid Screening study), utilizing both serum TSH and free T4 measurements to diagnose thyroid function abnormalities, indicate that the abnormalities tend to cluster around two main pregnant subpopulations 435. In about half the women with abnormalities, an isolated low serum free T4 level was found (defined as in the lowest 2.5th centile of normals) and an equal number of women having an isolated high serum TSH (defined as above the 97.5th centile of normals), with relatively few of them having both low T4 and high TSH.
  • 72. Figure 20: Study N°1 (N=726) showed thyroid abnormalities present in 16.5% of women; study N°2 (N=1.660) showed hitherto unknown thyroid dysfunction and/or thyroid autoimmunity features in 6.5% of women, with 1/5th of healthy pregnant women having a transient blunting in serum TSH. (from Glinoer, Refs 3, 24, 176, 209) Concerning the financial burden of thyroid testing, the latest calculations made for my country (Belgium) indicate that measuring TSH, free T4 and TPO-Ab amounts to a total cost of 38.40 € (i.e. ~50 US $). Patients who are covered by the national social security system (almost 100% of the population) would have to contribute 8.70 €, and the state would reimburse the difference to the laboratory (i.e. 29.70 €). When considering the average medical ‘cost’ of an uncomplicated pregnancy in our country (~2.500 €), the inclusion of thyroid screening would only add 1.5% to the overall cost. Concerning the screening procedures, several schemes can be proposed, although all encompass advantages and disadvantages that need to be carefully considered. The optimal timing of screening has not been determined, although there are good arguments to favor early screening. Immune suppression of autoantibody production points to the necessity to check the presence of TPO-Ab as early as possible during gestation 208, 212. On the other hand, the normal physiologic (transient) blunting in serum TSH near the end of 1st trimester makes the delineation of the optimal timing for TSH screening more complex. Therefore, nomograms or trimester-specific references for normality have been proposed by some authors to facilitate the interpretation of TSH changes during pregnancy 72-75. Measurements of serum free T4 can also be altered artefactually during pregnancy and this needs to be considered as well, as it might perhaps be minimized by using laboratory- specific or assay-specific or trimester-specific serum free T4 reference norms, that need to be locally established 66, 70, 72.
  • 73. Concerning benefits of treatment with regard to obstetrical outcome and fetal development, there is good evidence that they outweigh largely the risks associated with absence of treatment for overt hypothyroidism & hyperthyroidism (related mainly to GD) (see Table 14-16). Concerning subclinical hypothyroidism and thyroid autoimmunity features in women who have a normal thyroid function in early pregnancy, studies have now convincingly shown that early treatment with thyroxine was advantageous by restoring and/or maintaining euthyroidism throughout gestation 202, 225. Concerning subclinical hyperthyroidism (related mainly to gestational hCG-induced hyperthyroidism), advantages of treatment have not been demonstrated so far, except in severe cases with hyperemesis gravidarum. After screening, and notwithstanding the decision to treat a thyroid condition or monitor thyroid function, it is important to note that diagnosing chronic autoimmune thyroiditis also allows for delineating a group of women who are at risk of developing thyroid dysfunction during the postpartum period and hypothyroidism later in life 205. Table 14-16. Benefits of medical intervention for thyroid disorders during pregnancy Medical Intervention Benefits for Thyroxine treatment Mother Fetus Overt hypothyroidism +++ +++ Subclinical hypothyroidism + ? Thyroid autoimmunity (euthyroid) + ? Isolated hypothyroxinemia ? ? Antithyroid drugs Overt hyperthyroidism +++ +++ Transient gestational hyperthyroidism ? ? Subclinical hyperthyroidism - - Iodine supplementation (population) +++ +++ A recent publication by Dosiou et al. proposed the first cost-effectiveness analysis of screening pregnant women for thyroid autoimmunity and dysfunction 436. In this model, the authors evaluated three options: no screening, screening with TPO-Ab, or screening with TSH. The index case on which the model was based was a 25 year-old woman screened once in the 1st trimester. After initial screening, the authors selected various ‘strategy’ tracks in order to include serum re-testing, visits with an endocrinologist, follow-up and treatment when appropriate. Using available probabilities of thyroid function abnormalities and evaluation of financial costs implied by such procedures, the authors derived from their probabilistic approach a plausible evaluation of cost-effectiveness and concluded that screening in the 1st trimester was indeed cost-affective compared with not screening. Besides the evident issues of cost, practicality, or feasibility of systematic screening in pregnancy, some potential disadvantages must also be considered. For instance, the results of screening might induce unnecessary anxiety. Also, finding a low serum TSH (without hyperthyroidism) might be followed by the administration of antithyroid drugs, even when such treatment is not justified. Finally, there are also legal aspects to consider in this matter. If universal screening should become mandatory, then obstetric care providers may face the risk that any deviation from accepted guidelines might constitute a cause for legal suits.
  • 74. Policy considerations for systematic screening during pregnancy Policy considerations concerning universal routine thyroid screening before and/or during pregnancy remain controversial and are subject of heated debates, especially in the United States. Between 2000 & 2004, the American College of Obstetricians and Gynecologists (ACOG), the American Thyroid Association (ATA), and a consensus panel including the American Association of Clinical Endocrinologists (AACE), ATA, and The Endocrine Society (TES) has not endorsed the recommendation for routine screening of thyroid disorders in pregnancy. In their conclusions, the panel wrote that “there is insufficient evidence to recommend routine thyroid screening in pregnancy (or in women desiring pregnancy)” 437-439. Subsequently, the leadership of AACE, ATA, and ES has invited a second group to determine whether there were areas of legitimate and significant disagreement with the conclusions of the consensus panel. This group concluded their work “in favor of routine screening for subclinical thyroid dysfunction in adults, including pregnant women and those contemplating pregnancy” 440. In 2005, an international ad hoc committee was established under the auspices of the American Endocrine Society to review the best available evidence for thyroid disorders associated with pregnancy and develop evidence-based guidelines for clinical practice. Members of the ten-person task force (chaired by Leslie DeGroot) included representatives of TES, ATA, ETA, LATS, AOTA, AACE & ACOG. The issue of “universal screening” was hotly debated in this task force. One major consideration among the task force members was that negative outcomes had clearly been linked to thyroid function abnormalities associated with pregnancy and it was felt, therefore, that renewed attention should be focused on screening for thyroid dysfunction in the peri-partum period. Specifically, the association of infertility with thyroid autoimmunity and dysfunction, the association of an increased risk of miscarriage with thyroid abnormalities, the association of a poorer obstetrical outcome with thyroid dysfunction, the association of a decreased IQ in the offspring of mothers with subtle degrees of thyroid dysfunction, and finally the association of postpartum thyroid disorders with thyroid autoimmunity, contributed all to the apparent merit of universal screening. However after reviewing the available evidence, force was to admit that the overall lack of carefully conducted studies evaluating the impact of medical intervention on the negative outcomes associated with thyroid abnormalities during pregnancy and the postpartum precluded a recommendation for universal screening. As already alluded to above, individual members of the committee considered that there were enough valid arguments to believe that the evidence (albeit incomplete or indirect) was sufficient to justify screening before/during pregnancy. Finally, the task force came to the conclusion that “since it was not possible to recommend universal screening, an acceptable compromise is aggressive case finding; targeted case finding in high risk population may provide an appropriate balance between inaction and screening entire populations” (see Table 14-12) 1. More details can be found in the Section on ‘primary hypothyroidism’. On a more personal note, it is regrettable that ACOG did not, eventually, endorse the recommendations of the international guidelines committee. In a press release by ACOG in October 2007, their representatives wrote that “there is no evidence that identifying and treating pregnant women with subclinical hypothyroidism improves either maternal or infants outcomes” 441. We certainly agree that it can be argued that the high frequency of thyroid hormone and TSH determinations that are out of the ‘normal’ range, but normal for pregnancy, could constitute an adverse effect of systematic screening by health care
  • 75. providers other than endocrinologists 442. Such values could wrongly be misinterpreted by non-endocrine providers and result in unnecessary anxiety, referral, and even undue treatments for the pregnant woman. Alternatively and as already elaborated earlier, there are good arguments to advise that routine screening for thyroid disorders is warranted in the general population, and especially in pregnant women 440. In an editorial by the Editor of the Journal ‘Thyroid’, Terry Davies wrote that “to list so many reasons for testing women in a case-finding approach such that almost all women would be included is less satisfactory that leading and stating clearly that it is not appropriate to let pregnant women proceed without thyroid function testing. I doubt a single physician present at the Endocrine Society presentation would fail to screen a pregnant woman for thyroid disease. And that means that every obstetrician should be doing the same thing” 443. Present situation concerning screening An interesting study was recently conducted in the New Jersey/New York metropolitan area, with the objective to determine the level of knowledge of endocrinologists, obstetrician/gynecologists, internists, and finally family physicians in regard to thyroid disease and pregnancy 444. In this 16-item questionnaire, the questions asked concerned topics such as hypothyroidism and GD in pregnancy, thyroid autoimmunity and pregnancy, postpartum thyroiditis, risk of IQ impairment in the progeny of mothers with thyroid disorders, etc. A total of 412 physicians completed the questionnaire. Among them, percentages of physicians who treated pregnant women were 94% for the endocrinologists, 90% for the obstetricians/gynecologists, 58% for the internists and 68% for the family physicians. The main findings indicated a ‘disturbingly’ low level of knowledge in physicians across all disciplines. Knowledge gaps were mainly related to areas of relatively recent scientific new acquisitions, but also to facts that have been known for decades. Endocrinologists scored highest with 77% of correct responses to the questionnaire. Two questions, for instance, dealt with Graves’ disease (on the natural course of the disease and the goal of treatment with antithyroid drugs). Correct response rates to these questions were 71% for the endocrinologists, but only less than 50% for the obstetricians/gynecologists and also less than 40% for the family physicians. The overall low scores may be attributed to a lack of adequate education on thyroid disease during pregnancy, lack of exposure to women during pregnancy, or the inability to translate research information into clinical practice. Thus when discussing the pros and cons of systematic screening during pregnancy, one must take into account that the main challenge is to translate new research-derived information into clinical practice, and this goal can only be achieved through education of the various medical professions involved with the care of pregnant women. Irrespective of the opinions of some scientific societies, the practice of screening pregnant women for thyroid disorders has already been adopted in many university hospital centers, mainly (but not only) in Europe. A survey by Haddow et al. indicates, for instance, that many practitioners in Maine have also instituted routine TSH testing in pregnancy, in spite of a lack of consensus among professional organizations 445. Is a case-finding approach sufficient? This question has been recently evaluated by Vaidya et al. in the UK in a study wherein screening pregnant women classified as ‘high-risk’ was evaluated 446. High-risk women were defined on the following criteria: a personal history of thyroid disorders including women with thyroid treatment, a personal history of type 1 diabetes and/or other autoimmune disorders, and finally a family history of thyroid disorders. The authors showed that the use of high-risk criteria allowed only for the detection of 70% of women with hypothyroidism, while high-risk criteria were no better than low-risk criteria for the identification of women with a suppressed serum TSH (see Figure 14-21).
  • 76. In summary from the few studies available, it seems reasonable to conclude that there are obvious shortcomings in a targeted approach to screening. Therefore, such strategies should remain considered as partial solutions, at least until more data become known to us in order to fine-tune benefits of universal screening of women for thyroid disorders during pregnancy 1, 434, 447. Normal TSH ↑ TSH ↓ TSH (> 4.2 mU/L) (L-D + F-S) High-risk 348 28 (6.8%) 28 + 9 (9.0%) (n = 413) Low-risk 1.051 12 (1.0%) 64 + 20 (7.3%) (n = 1.147) All women 1.560 40 (2.6%) 92 + 29 (7.8%) (n = 1.560) High versus low risk ♀ : RR = 6.5 (95% CI: 3.3-12.6; P < 0.0001) Figure 21: 413/1.560 women corresponded to the ‘high-risk’ criteria, representing 25.6% of the screened population. For a suppressed serum TSH, the authors examined 2 subgroups: women with a low but still detectable serum TSH (column ‘L-D’ in figure) and with a fully suppressed serum TSH (column ‘F-S’ in figure). Percentages of ‘positive’ detection were not different among the different risk groups for a low TSH. For a raised serum TSH, percentages of ‘positive’ detection were significantly higher in high-risk women, but the data also showed that approximately one third of women with an abnormally elevated serum TSH would still have been missed if the screening procedure had only concerned such women. (from Vaidya et al., Ref 446)
  • 77. FINAL CONCLUSIONS Pregnancy has profound effects on the regulation of thyroid function in healthy women and patients with thyroid disorders. These effects need to be recognized, precisely assessed, clearly interpreted, and correctly managed. For healthy pregnant women who reside in areas with a restricted iodine intake, relative hypothyroxinemia & goitrogenesis occur frequently, indicating that pregnancy constitutes a challenge for the thyroidal economy. Overt thyroid dysfunction occurs in 2-3% of pregnancies, but subclinical thyroid dysfunction (both hyper- & hypothyroidism) is probably more prevalent and frequently remains undiagnosed, unless specific screening programs are initiated to disclose thyroid function abnormalities in early gestation. Maternal alterations of thyroid function due to iodine deficiency, hypothyroidism and hyperthyroidism have important implications for fetal/neonatal outcome. In recent years, particular attention has been focused on potential developmental risks for the fetuses of women with hypothyroxinemia during early gestation. Pregnancy increases the metabolic rate, blood flow, heart rate, and cardiac output, and various subjective sensations such as fatigue and heat intolerance that may suggest the possibility of coexistent thyrotoxicosis. Other metabolic changes which also impact the hypothalamic pituitary thyroid system are the potential direct stimulation of the maternal thyroid by hCG, as well as the accelerated metabolism of thyroxine, presumably due to increased placental deiodination enzymes. In patients with hypothyroidism, it is important to recognize that therapeutic requirements for exogenous thyroxine are increased by 50% on average during pregnancy. This should be taken into account in the management of such patients. Main causes of thyrotoxicosis in pregnancy include Graves' disease (uncommon, but potentially pregnancy-threatening) and gestational non autoimmune transient hyperthyroidism (more common, but remaining mild usually). The natural history of Graves' disease is altered during pregnancy, with a tendency for exacerbation in 1st trimester, amelioration during 2nd & 3rd trimesters, and typically a rebound during the postpartum period. These changes are the consequences of partial immune suppression during gestation with a rebound during the postpartum period. This must be kept in mind when treating thyrotoxic patients, since all ATD cross the placenta and may affect fetal thyroid function. Fetal and neonatal hyperthyroidism is due to the transplacental transfer of maternal stimulating TSH-receptor antibodies (TRAb). The diagnosis of fetal (and neonatal) hyperthyroidism is usually made on the basis of fetal tachycardia, accelerated bone age, and intrauterine growth retardation. It may occur in infants born to women with active Graves' disease, but also to women who have had prior definitive cure of their disease by surgery or radioactive iodine, but maintain high titers of TRAb. The proper management of pregnant patients with Graves' disease remains a difficult challenge in clinical endocrinology. Thyroid nodules discovered during pregnancy should be aspirated for cytological diagnosis. If a malignancy is diagnosed, surgery should be performed during pregnancy or shortly thereafter. Pregnancy by itself does not adversely affect the natural history of differentiated thyroid carcinoma. During the postpartum period, particular attention should be given to women with thyroid autoimmunity, since hypothyroidism and hyperthyroidism are frequently exacerbated in the months following the delivery.
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