Iodine and Pregnancy

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 1,2. Figure 14-1 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.

Figure 14- 1

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 1).

Early in pregnancy there is an increase in renal blood flow and glomerular filtration which lead to an increase in iodide clearance from plasma (1,16). This results in a fall in plasma iodine concentrations and an increase in iodide requirements from the diet . 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. 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 (17).

In regions where the iodine supply is borderline or low, the situation is clearly different and significant changes occur during pregnancy (1). Historic studies of radioiodine uptake have shown an increase (18). In addition, there is a further increment in iodine requirements, due to transplacental iodide transport necessary for iodothyronine synthesis by the fetal thyroid gland (19), which becomes progressively functional after the first trimester. When pregnancy takes place in conditions with borderline iodine availability, significant increments in both maternal and fetal thyroid volume occur, if no supplemental iodine is given during early pregnancy (20).

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 deficiency present at critical stages during pregnancy and early childhood results in impaired development of the brain and consequently in impaired mental function (8,21). Iodine deficiency worldwide is a major cause of neurointellectual impairment and is discussed in detail in chapter 20.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. A WHO committee recommended appropriate iodine intakes for pregnant and lactating women as well as for children (Table 14-2) (22)

Table14- 2. Recommended iodine intake during pregnancy and lactation and categorization of iodine nutrition adequacy based on urinary iodine excretion

Patients with known or underlying autoimmune thyroid disorders or autonomous thyroid tissue may have side effects from excessive iodine intake, There is no clear evidence to define “how much more iodine may become too much iodine.” A recommendation was adopted to indicate that there is no proven further benefit in providing pregnant women with more than twice the daily RNI (recommended nutritional intake).

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).

Although substantial progress has been made in the worldwide correction of iodine deficiency mainly by increasing the universal salt iodisation Nevertheless there have been many studies and reports from different world regions demonstrating the resurgence of iodine deficiency in pregnant women despite previous successful public health strategies to correct population deficiencies of the element. Therefore iodine deficiency requires constant monitoring, even after the implementation of iodine supplementation in pregnant women. Recently, iodine deficiency has re emerged in Australia and the UK and even in USA there are groups of the population with suboptimal iodine levels (24-26). The importance of iodine deficiency in pregnancy on childhood IQ has been emphasized (27). In addition there is increasing evidence of the benficial effect of iodine supplementation before and during pregnancy in ameliorating this problem (27)

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 14-2 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 14-2; 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 still seen in parts of Western Europe), the system must up-regulate the glandular iodide trapping mechanisms and increase the relative iodine intake to 50 (Figure 14-2; panel B). The higher uptake allows to recover 35 µg of 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 (27).

Figure 14-2

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 27).

Goiter Formation In Mother And Progeny

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 (1). Pregnancy may therefore be considered as an ‘environmental’ factor to induce thyroid pathology in areas with a marginally reduced iodine intake. 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 (1). 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 (28). 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 (29,30). 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 (31). In fact there is a high prevalence of thyroid disorders in this region associated with mild iodine deficiency (32). 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) (33).

Goitrogenesis associated with pregnancy may be one of the environmental factors explaining the preponderance of goiters in the female population. There is an association between parity and thyroid volume in an iodine deficient area (34) and this may be accentuated by active smoking(35) Rarely, a pre-existing goiter may increase in size abruptly during gestation, leading to tracheal compression and respiratory symptoms due partly to intrathyroidal hemorrhage (36,37).

The biochemical markers of enhanced thyroidal stimulation during an otherwise normal pregnancy, when iodine deficiency is present. are firstly relative hypothyroxinemia ( serum free T4 concentrations near (or below) the lower limit of the gestational reference range); Preferential T3 secretion (reflected by an elevated total T3/T4 molar ratio) and a progressive rise in TSH to reach levels that are twice (or even higher) the preconception serum TSH levels (38). In mild to moderate iodine deficiency conditions, serum thyroglobulin (Tg) increases progressively during gestation, so that at delivery, two thirds of women may have supra-normal Tg concentrations. Tg increments correlate well with gestational goitrogenesis, and hence constitute a useful prognostic marker of goiter formation, and its prevention by iodine supplementation (33). 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. Therefore, in the individual at risk of iodine deficiency the markers of thyroid stimulation already described are the best indicators of thyroid stress.

Treatment and Prevention of Maternal Goiter in Pregnancy

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. he importance of continuing monitoring of iodine status in the population cannot be overemphasized and has been discussed above.

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 15-20 years ago worldwide, based on universal salt iodization (USI), and that has shown remarkable progress so far (33). However, 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 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 [Fig 14-3] 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 (33). Even then, despite iodine supplementation, iodine sufficiency may not be attained by all pregnant women (40). Because of the advocacy for salt restriction to reduce cardiovascular mortality a debate has ensued whereby use of iodinated salt seemed to be at odds with this strategy. However, simply increasing the iodine concentration in the salt can accommodate both the reduction in salt intake and the requirement to provide iodine in this way. This strategy has recently been endorsed by WHO (41).

Importantly, it has also emerged that insufficient iodine status is associated with poorer neurocognitive outcome in the offspring. While this has been accepted for many decades in relation to severe iodine (42) deficiency it is now seen to be the case in areas of mild iodine deficiency (43-45). The is accruing evidence that iodine supplementation in pregnancy even in women with mild iodine deficiency is beneficial in improving neurocognitive outcome in the child (46).

Finally, caution is needed to avoid iodine excess to the fetal (47) as well as the maternal (48) 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 (49).

Figure 14-3

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 33).

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 (8). 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 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 (50, 51).

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. Iodine prophylaxis is best achieved using iodised salt. An equal if not more important benefit of using salt supplementation in gestation is the demonstrable positive effect on neurocognition in the child in areas of iodine deficiency or any degree. Monitoring of the population with urinary iodine measurements is essential.

Effects Of human Chorionic Gonadotrophin On Thyroid Function

Human chorionic Gonadotrophin (hCG) is a member of the glycoprotein hormone family that is composed of a common α-subunit and a non-covalently associated, hormone-specific β-subunit. The α-subunit of hCG consists of a polypeptide chain of 92 amino acid residues containing two N-linked oligosaccharide side-chains. The β-subunit of hCG consists of 145 residues with two N-linked and four O-linked oligosaccharide side-chains. The β-subunit of TSH is composed of 112 residues and one N-linked oligosaccharide. The β-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 αsubunit, while the genes that encode for the β-subunits are clustered on chromosome 19, with seven genes (but only three actively transcribed) coding for β-hCG (52).

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 (52). 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 (1,52.) 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 fig 14- 4. 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 at 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 (53)

Figure 14-4

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 53).

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 54. 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 (55).

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 (1). The cause of the marked increase in serum TBG is probably multifactorial. TBG biosynthesis was increased, after estradiol priming, in primary cultures of hepatocytes from Rhesus monkeys (56) and 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 (57). 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. (57). 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 (58). 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 (59) 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. Delivery leads to a rapid reversal of this process and serum TBG concentrations return to normal within 4-6 weeks. 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.

In a 42-year-old woman who had both established hypothyroidism and inherited TBG deficiency, the baseline TBG level was 70% below the average baseline level of non-TBG-deficient women (60).. 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. It was suggested therefore that an increase in TBG concentration was not the key determinant for the increase in thyroxine requirement in pregnancy. However, an alternative explanation was proposed (61). 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 14-5). In the exceptional case of Zigman, when this partially TBG-deficient patient was not pregnant, her serum total T4 was ~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.

Figure 14-5

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.

The Placenta

During the first trimester the human conceptus is surrounded by the placenta, which acts as an exchange unit for nutrients and waste products. The primary barrier to exchange between mother and fetus is the syncytiotrophoblast layer of the placental chorionic villi which has effective tight junctions and prevents the free diffusion of thyroid hormones across it.

The human placenta in addition to this cellular barrier also regulates the amounts of thyroid hormones passing from the mother to the fetus through its expression of placental thyroid hormone transporters, thyroid hormone binding proteins, iodothyronine deiodinases, sulfotransferases and sulfatases (63,64). The transport of iodine through the placenta is also important as the organ has shown to actively concentrate the anion (65). Oxytocin and hCG may also promote placental iodide uptake helping to protect against fetal iodine deficiency(66) Placental NIS protein levels are significantly correlated with gestational age during early pregnancy and increase with increased placental vascularization. This would lead to increased iodide supply to meet increased fetal requirements for thyroid hormone synthesis as the pregnancy progresses (67) The precise details of placental iodide concentration are unclear. It is interesting that in mothers who smoke placental iodide transport seemed unaffected despite high thiocyanate levels, suggesting that thiocyanate-insensitive iodide transporters alternative to NIS are active or that NIS in the placenta is autoregulated to keep iodide transport unaltered.(68).

Fetal circulating concentrations of total T3 are at least 10 fold lower than total T4. Unlike adults, the proportion of free unbound T4 is also higher than bound T4 in early gestation. Free T4 levels are determined by the fetal concentrations of the thyroid hormone binding proteins in the circulation and coelomic cavity and the amount of maternal T4 crossing the placenta. The concentration of free T4 in the coelomic fluid in the first trimester is approximately 50% of that found in the maternal circulation and could therefore exert biological effects in fetal tissues.

The human placenta expresses iodothyronine deiodinases type II (D2) (which activates T4 to T3) and type III (D3) (which inactivates T4 and T3). The principle subtype in the placenta is D3, having 200 times the activity of D2. D3 effectively metabolises most of the maternal T4 presented to the placenta.: still a physiologically relevant amount of T4 is transferred to the fetus. Both D2 and D3 activity per gram of placenta decrease with advancing gestation.( 64). Decidualization, which is a characteristic of the endometrium of the pregnant uterus and a response of maternal cells to the hormone progesterone, is also dependent on the strong expression and tight control of the type 3 deiodinase (69) to regulate the local T3 concentration.

A range of thyroid hormone transporters including monocarboxylate transporters (MCT) 8 and 10, system-L amnio acid transporters (LAT1 and LAT2) and organic anion transporting polypeptides (OATP) 1A2, 4A1 and Oatp1c1 have been located at the apical and basolateral membranes of the syncytiotrophoblasts (70,71). These transporters may facilitate thyroid hormone transfer across the cell barrier from the mother to the fetus ( Figure 14-6). In fact, it seems that the syncytiotrophoblast may control the quantity and forms of thyroid hormones taken up by the human placenta so that this this could be critical in regulating transplacental thyroid hormone supply from the mother to the fetus (72). Studies in the mouse with human placental tissue indicate that MCT8 makes a significant contribution to T3 uptake into human trophoblast cells and has a role in modulating human trophoblast cell invasion and viability (73). Transthyretin (TTR), a serum thyroid hormone binding protein, appears to play an important role in the delivery of maternal thyroid hormone to the developing fetus. (74).The human placenta secretes TTR into maternal and fetal circulations and the placental TTR secreted into the maternal placental circulation can be taken up by trophoblasts and translocated to the fetal circulation, forming a TTR shuttle system. This may have important implications for materno-fetal transfer of thyroid hormones (75).

Fig 14-6

The passage of T4 and T3 from the maternal to fetal circulation requires negotiation through the apical membrane (maternal-facing) and the basolateral membrane (fetal-facing) of syncytiotrophoblasts (ST), and in the first half of pregnancy (A) through the plasma membranes of cytotrophoblasts (CT) as well. The localisation and function of the six different TH transporters ( ) present in the placenta may differ. These include monocarboxylate transporters (MCT) 8 and 10, system-L amnio acid transporters (LAT1 and LAT2) and organic anion transporting polypeptides (OATP) 1A2 and 4A1.There may also be other yet to be identified TH transporters. In addition, T4 and T3 are subject to metabolism by deioidnase type 2 (D2) and type 3 (D3) as they pass through the trophoblasts. (From 63)

In addition to the regulation of transplacental thyroid hormone transfer for fetal development, human placental development is itself is responsive to thyroid hormone from early in gestation with evidence of trophoblastic expression of thyroid hormone receptors. T3 has been shown to promote proliferation, invasion and production of epidermal growth factor by 1^st trimester primary trophoblast cultures. In humans T3 has been shown to suppress apoptosis and down regulate Fas and Fas-ligand expression (76). It has been postulated that abnormal thyroid hormone levels could give rise to malplacentation which underlie the association between maternal thyroid dysfunction and adverse obstetric outcome.

The inner-ring deiodination of T4 catalyzed by the type 3 deiodinase enzyme is the source of high concentrations of reverse T3 present in amniotic fluid, and the reverse T3 levels parallel maternal serum T4 concentrations (77). 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). 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.(78). Thyroxine can be detected in amniotic fluid prior to the onset of fetal thyroid function, indicating its maternal origin by transplacental transfer (79).. Figure 14-7 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. (Because of low levels of binding proteins in the amniotic cavity, the ratio of amniotic/serum FT4 is much higher.) 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 (63). 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.

Figure14- 7Steep gradient between maternal concentrations of thyroid hormones (Total T4) and those measured in the coelomic fluid and amniotic cavity with the developing embryo, during early stages of gestation.

A review concluded that a local action of thyroid hormones on female reproductive organs and embryo seemed to be crucial for a successful pregnancy and alterations of the highly regulated local activity of thyroid hormones may play an important, previously underestimated role in early pregnancy and pregnancy loss (80). Furthermore, studies in rats suggest that transcriptomic profiling of the utero-placental compartments, in addition to analysis of mRNA expression of key thyroid hormone placental signaling genes, may predict offspring obesity (81) It is important to note that there is increasing evidence that placental and angiogenic factors are affected by thyroid hormones (82). In isolated human decidual cells T3 regulates angiogenic growth factor and cytokine secretion in a cell-type specific and gestational age specific manner(83). In a large number of women from the Generation R study it was found that high levels of pro- and anti-angiogenic factors may be a risk factor for adverse pregnancy outcomes through their effects on maternal thyroid function (84). Overall thyroid hormones modulate inflammatory processes and are implicated in placental development and disease (85).

Immunological and hormonal aspects of normal pregnancy (Table 14-3)

Pregnancy has a significant effect on the immune system, in order to maintain the fetal-maternal allograft, which is not rejected despite displaying paternal histocompatability antigens. While there is no overall immunosuppression during pregnancy, clinical improvement usually occurs in patients with immunological disorders such as rheumatoid arthritis (RA) when they become pregnant. Clinical improvement occurs as well in psoriatic arthritis and Graves' disease. On the other hand, systemic lupus erythematosus (SLE) may flare during pregnancy.

Table 14-3 Immunological and Hormonal Features of Pregnancy

Clinical: Improvement in Graves’ hyperthyroidism

Rheumatoid arthritis

Psoriatic arthritis and other autoimmune diseases

Trophoblast: HLA G expression

Fas ligand expression

Lymphocytes: Th2 response

Th2 cytokines produced by the fetal/placental unit

Critical role of Treg cells (CD4⁺CD25⁺) in maternal tolerance

Possible role of Th17 lymphocyte subset

Hormones: Progesterone increase – reduction in B cell activity

Oestrogen increase – Fall in autoantibody levels

Cortisol,1,25 vitamin D and norepinephrine all affect the immune response

Other Galectin-1

The trophoblast does not express the classical major histocompatibility complex (MHC) class Ia or II which are needed to present antigenic peptides to cytotoxic cells and T helper cells respectively. Instead HLA-G, a non-classical MHC Ib molecule is expressed which may be a ligand for the natural killer (NK) cell receptor so protecting the fetus from NK cell damage ; it may also activate CD8+ T-cells that may have a suppressor function. Human trophoblasts also express the Fas ligand abundantly, thereby contributing to the immune privilege in this unique environment possibly by mediating apoptosis of activated Fas expressing lymphocytes of maternal origin.

T-cell subset studies in pregnancy are discrepant, as peripheral blood CD4+ and CD8+ cell levels have been variously reported to decline, remain unchanged and increase during pregnancy. Although, the distinction between Th1 (T cell helper 1) and Th2 (T cell helper 2) immune responses in humans remains less clear than in the mouse the general agreement is that in pregnancy there is a bias towards a Th2 response (3) This seems to be achieved by the fetal/ placental unit producing Th2 cytokines, which inhibit Th1. Th1 cytokines are potentially harmful to the fetus as, for example, interferon alpha (IFNα) is a known abortifacient. The characterisation of regulatory T cells (CD4⁺CD25⁺), a T cell subset that can prevent experimental autoimmune disease, has improved the understanding of the immunological maintenance of pregnancy. It is now thought that these cells are one of the main groups of T cell subsets which allow tolerance of the fetal semi allograft. They may be found in the decidua as well as in the maternal circulation and regulate autoimmune responses.(3)

Assessment of Thyroid Function in Pregnancy

As there is significant overlap between the symptoms experienced by normal euthyroid pregnant women and those with thyroid dysfunction clinical diagnosis is not always straightforward. Because thyroid physiology is altered in pregnancy it has become clear during the past decade that normative gestational reference ranges for thyroid hormone analytes are necessary. Most clinical laboratory reports only provide non-pregnant reference intervals for the interpretation of laboratory results...

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 14-8, upper left panel) . If one uses total T4 to estimate thyroid function, the non pregnant reference range (5-12 µg/dl; 50-150 nmol/L) can be multiplied t by 1.5 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 14-8, upper right panel) . Thus, the use of total T4 does not provide an accurate estimate of thyroid function during early gestation.. However, the free thyroxine index (“adjusted T4“) appears to be a reliable assay during pregnancy (87).

Figure 14-8

Upper left panel: pattern of changes in serum TBG concentrations (mean + sd) in 606 normal pregnant women ( Ref 1). Upper right panel: pattern of changes in serum total T4 concentrations (individual results) in 98 normal pregnancies ( Ref 86). 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 . 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 (Ref 86). Lower right panel: pattern of changes in serum free T4

Although gestation specific reference intervals for thyroid function tests are not currently in routine use in most laboratories there has been intense activity world wide in the development of such ranges (4). . 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 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 (88). 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).

Unfortunately, few if any FT4 immunoassay manufacturers provide appropriate normal pregnancy-related reference intervals that are method-specific (specific for the method used for hormone analysis). It is therefore imperative that method- and gestation-specific reference intervals for FT4 are derived in the appropriate reference populations to prevent misinterpretation of thyroid status in pregnant women. While ‘gold standard methodology’ (e.g. tandem mass spectrometry) is useful for accurate standardisation of values (89), in practice the use of kit assays for free thyroid hormones as well as routine estimation of total bound hormones are used. These are based on analogue methods that rely on the concentrations of binding-proteins, are method-dependent and may give misleading FT4 and FT3 values in pregnancy. For example a commercially available FT4 assay has shown that it correlates more closely to total T4 assays than to FT4 measured following physical separation from binding proteins (90). A comparison of 5 different commercial assays for FT4 and FT3 showed significant interassay variation underlining the necessity for individual laboratory based reference ranges (91). Reference values for FT4 were different when measured by 7 different kits(92).Even in the same region, the use of gestational age specific reference ranges from different laboratories led to misclassification (93). FT4 assays are considered to be flawed and unreliable during pregnancy (87) but there are data showing that, despite susceptibility towards binding protein alterations, these assays may indeed reflect the gold standard assays (94). A mathematical analysis of measurement of total T4 or Free T4 in pregnancy concluded that free hormone measurement is indeed as good as the total assay (95). Gestational reference ranges for theses hormones as well as TSH should be available in every hospital dealing with pregnancy. (4). Table 14-4 shows selected reference ranges for FT4, FT3 and TSH published up to 2008. Since 2008 further country data has been documented (103-107). with emphasis being placed on obtaining first trimester ranges . Concern has been noted with regard to previous suggestions that the upper limit for TSH should be 2.5mIU/L in the first trimester(108) because of ethnic variation(109). A more realistic figure may be 3.0-4.0 mIU/L(110).

Table 14-4

Selected Trimester-Specific, Method-Specific FT4, FT3 and TSH Medians (±SD) or Means* (±SE) and Reference Intervals

In general, serum TSH concentrations provide the first clinical indicator for thyroid dysfunction. Due to the log-linear relationship between TSH and FT4, very small changes in T4 concentrations will provoke very large changes in serum TSH. However, in pregnancy, thyroid and pituitary functions are less stable. During early gestation, TSH is suppressed by 20-50% by week 10 due to the steep increase in hCG concentrations. Therefore, maternal serum TSH does not provide a good indicator for the control of treatment of thyroid dysfunction in the first trimester unless trimester specific ranges are available. False readings can lead to maternal under-replacement with LT4, or overtreatment with anti-thyroid drugs both of which can result in both maternal hypothyroidism and an increased risk for adverse fetal brain development. TSH is however the best measure of thyroid function during the 2^nd and 3^rd trimesters

Reliable trimester-specific (or gestation-specific) reference intervals for TSH are also now available, being based on an adequate sample size comprised singleton pregnancies in an iodine sufficient, antibody-free population ( see fig 14-9) The importance of the reference range is shown by the fact 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. The individual genetic set-points of a population may result in an intra-individual variability of the thyroid hormone levels, reflected by the reference intervals (112). Also, Afro Americans in USA have lower TSH values in gestation (113), and data from The Netherlands has also documented ethnic differences in thyroid function tests in pregnancy (114). These should be recognized when deriving normative reference ranges.

Figure 14-9

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 111).

In summary, TSH levels may be misleading in the first trimester and T4 values either total or free will give a more accurate estimate of clinical status. Later in gestation TSH levels are reliable whereas T4 may fall especially in the 3^rd trimester but this does not indicate hypothyroidism. In some cases, serum anti-TPO antibodies, anti-Tg and/or TSH receptor antibody levels can provide other information; TPO antibodies can predict the risk of hypothyroidism. Ethnic differences in trimester specific reference ranges should be noted. For example the upper limit of TSH in the first trimester was much higher than 2.5 mIU/L in Chinese pregnant women(108). Large differences in thyroid function reference intervals between different populations of pregnant women are seen due to assay variation as well as ethnicity and body mass index (115,116) In pregnant women with low TSH hyperthyroidism, TSH receptor antibodies are observed in 60–70% of the cases.

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 (117). Hyperemesis is associated with high hCG levels occurring at this time, but the exact cause remains uncertain. For unknown reasons, HG is more prevalent in Asian than Caucasian women. Norwegian data from 1967 to 2005 showed a prevalence of 0.9% but it affected 2.2% of Pakistani women; 1.9% of Turkish women and 0.5% of Norwegian women (118); a familial aggregation suggesting strong evidence for a genetic component of HG. has been suggested (119) When the charge-isoforms profiles of circulating hCG were compared in HG women with different ethnic backgrounds (Samoan vs. European). 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 matched control subjects was noted (120). The same study also confirmed the known association between hCG concentrations in early pregnancy and elevations in thyroid hormone levels .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 (121)

Thirty to sixty percent of patients with HG have elevations of serum free thyroid hormone concentrations with a suppressed TSH . 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 ‘gestational hyperthyroidism’ or ‘gestational transient thyrotoxicosis’ (GTT). Graves’ disease can also occur coincident with hyperemesis . 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

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 (52).. A case of severe HG was reported where the gestational thyrotoxicosis associated with HG was due to a mutation of the TSH receptor, providing hypersensitivity to hCG (122 ). Only one other similar case has since been reported world wide (123). 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 (124) Severity of emesis was correlated with serum free T4 and hCG levels and inversely with the degree of TSH suppression (124), suggesting strongly that HG may reflect the extreme end of the spectrum of physiological changes that occur at this time in normal pregnancy (Fig 14-10). It is possible 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.

Figure 14-10

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 (thanks to Carole for allowing me to borrow the slide). The figures are based on studies by Goodwin (Ref 118)

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 immunological test results, including anti-phospholipid, anti-nuclear antibodies and organ specific autoimmunity, among which the presence of antithyroid antibodies (127-129). However, In women with reproductive failure the presence of autoantibodies does not appear to affect the numbers of K cells in the endometrium around the time of implantation (130). In women with repeated implantation failure the percentage of cytotoxic T cells was increase in those with thyroid autoimmunity compared to those without (131).

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 (132,133). Although many of the studies relating to the association of thyroid antibodies and infertility are subject to selection bias, retrospective analysis, and different causes of infertility, they broadly confirm the association. Analysis of a large Danish population (11254 women) has shown that impaired fertility is associated with TSH, TPOAb and subclinical hypothyroidism (134). A previous large study employing control women study has documented an OR of 2.1 (1.7-2.6), p< 0.0001, in favour of the association of infertility and thyroid antibodies (135). Medically-assisted conception and onset of gestation is not hampered by AITD, but a successful outcome of the ongoing pregnancies is significantly reduced in those women with AITD due to greater early pregnancy loss (see Figure 14-23) (136)

The mechanism of the association between thyroid antibodies and infertility is not clear. A review has noted that thyroid hormone disorders and TPOAb are associated with disturbed folliculogenesis,spermatogenesis, fertilization and embryogenesis but the pathogenesis of TPOAb and reproduction is not well understood (137). It is of interest that there is an increase in infertility in women with endometriosis [RR 3.57] (138) which is known to have immune cell depression (NK cells), as well as decreased activity and cytotoxicity against autologous endometrium (139). The importance of NK cells has been emphasised (139) and impaired cellular and humoral response in women with unexplained infertility has been shown (140). The demonstration of antithyroid antibodies in ovarian follicles (141) may also suggest a critical role in infertility associated with autoimmune thyroid disease. These conclusions are strengthened by a study in mice in which it was noted that the anti TPO antibody may affect post-implantation embryo development leading to fetal loss (142). Lack of vitamin D was suggested as a predisposing factor to autoimmune diseases, and was shown to be reduced in patients with thyroid autoimmunity. In turn, its deficiency is also linked to infertility and pregnancy loss, suggesting a potential interplay with thyroid autoimmunity in the context of infertility (143)

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.Screening for thyroid function in infertile women should be routinely performed (144,145) 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 (146). It should be noted that in a study of 21 thyroxine treated women compared to 219 euthyroid women, women with hypothyroidism had a significantly decreased chance of achieving a pregnancy following IVF compared to euthyroid patients (147). The reasons are unknown and more data are required. Controlled ovarian hyperstimulation studied in 57 women led to significant elevations in TSH, often above pregnancy appropriate targets. These findings were particularly evident in women with preexisting hypothyroidism and may have important clinical implications for screening and thyroid hormone supplementation (148) 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).

Figure 14-12

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 136).

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(2). . 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.(149)

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.) (150).

Stagnaro-Green (151) reported a doubling of the spontaneous miscarriage rate in women who were Ab+ve compared with an Ab-ve cohort (17 vs 8.4%; p = 0.001). Subsequent meta analyses confirmed these associations (152,153). In a further 22 studies up to 2007 with only 6 showed no statistical correlation between the presence of antibodies and miscarriage (154). High TSH levels in women without overt thyroid dysfunction are associated with miscarriage but maternal FT4 levels and child loss were not associated (154). In 101 women with a TSH level more than 20mIU/L treated with T4 adverse pregnancy outcomes occurred no more frequently than in a control group of 205 euthyroid women. However the TSH level during pregnancy was correlated with the rate of abortion and premature delivery (155). In 216 women known to have had a miscarriage before 12 weeks gestation autoimmunity was independently associated (156). A meta analysis of 21 studies (13 cohort and 8 case control) showed a pooled odds ratio of 2.55 [CI 1.42-4.57 p=0.002] (157). A large study in which 17,298 women were screened for thyroid autoimmunity (158) showed a 3 fold increase in placental abruption in the 6% who were antibody positive (OR 3.4 CI 1.7-6.7). This 3 fold risk of placental abruption has been confirmed by a further meta analysis of 31 studies (159) involving more than 12000 women. Meta analysis of both the cohort (n=19) and case-control studies showed a positive association of thyroid antibodies with pregnancy loss (OR 3.9 CI: 2.48-6.12 p<0.001) for cohort studies and 1.8 (1.25-2.6 p,0.002) for case-control studies. A similar OR was found by a Dutch review (3.73 95% CI 1.8-7.6) (160). The 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. In contrast an observational study of 220 women with recurrent miscarriage with TPOAbs compared to 496 women with miscarriage but no antibodies it was found that the prevalence of TPOAb in women with unexplained RM was not higher than in the general population, TPOAb-positive status did not have a prognostic value regarding the outcome of a subsequent pregnancy, and empirical thyroxine therapy in those who tested positive did not seem to improve outcome (161).However a systematic review has suggested that L Thyroxine does indeed reduce miscarriage rates (162). The American Society of Reproductive medicine asserts that there is fair evidence that thyroid autoimmunity is associated with miscarriage and that L-Thyroxine may improve pregnancy outcomes especially if TSH is > 2.5mIU/L (145).Miscarriage may be linked to a generalized immune imbalance. Women who have had multiple miscarriages have an increased number of CD5/20+ B cells compared with women who have had one or none (163).. 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 (164).However, evaluation of thyroglobulin expression in reproductive organs of mice showed no message in placenta, decidua or ovary suggesting that antithyroglobulin antibodies have no direct detrimental effect on such organs in patients with thyroid autoimmunity suffering from recurrent abortion (165).On the other hand Ticconi et al (166) in a case control study of 160 women with recurrent miscarriage (RM) found both TPO and Tg antibodies to be more frequently present than in 100 healthy pregnant women. Importantly, more than 90% of the RM women had evidence of other autoantibodies suggesting a more general maternal autoimmune defect in RM.

AITD may be associated with inappropriate low levels of thyroid hormones for the given gestational period, despite apparent biological euthyroidism. 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 (167). Women with AITD are generally older than healthy controls and increased age is an independent risk factor for miscarriage. AITD could act therefore 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. There are no clear answers to the problem of thyroid autoimmunity and miscarriage and the subject has been reviewed (168).

Women Undergoing IVF

Different regimes of IVF are now frequently employed in infertile women and new approaches to ovarian stimulation are being implemented (169). A meta analysis of 4 studies on 1098 subfertile women (170) with thyroid autoimmunity and 957 controls showed an RR for miscarriage of 1.99 (CI 1.416-2.793, p<0.001) [ Fig 14-24].

Therefore, on current evidence, it does appear that the presence of thyroid autoimmunity is associated with an increased risk for spontaneous miscarriage in subfertile women achieving a pregnancy through an IVF procedure.(136,170-175); however the clinical picture is not clear cut .Negro et al. (176) found that pregnancy rates were not affected by the presence of TPOAb in euthyroid women undergoing assisted reproductive technology (ART). Intracytoplasmic sperm injection is a relatively new method of ferilisation. Studies of patients with thyroid autoimmunity and thyroid antibodies (anti TPO) concluded that these abnormalities did not affect cumulative delivery rates, fertilization, pregnancy rates, live birth rates or miscarriage rate compared to women without thyroid autoimmunity (177-179). Successful modulation of the immune system with beneficial pregnancy outcome has been reported in patients with AITD who received immunoglobulins with (or without) additional heparin or aspirin (180-182). However, the sudies were not adequately controlled, only comprising small numbers of patients who also had othe, auto-antibodies other than thyroid antibodies.

Fig 14-24

Miscarriage risk in euthyroid women with thyroid autoimmunity undergoing IVF. % weight refers to the emphasis placed on each of the 4 studies used in the analysis. From (170)

It is possible that TPOAb+ve women could have a better outcome with IVF if they also received LT4 as well as aspirin and prednisone (183) When 50 micrograms of LT4 was administered to women with subclinical hypothyroidism undergoing IVF showed an improvement in embryo quality and pregnancy outcome (184). A retrospective cohort study has confirmed that the vast majority of hypothyroid treated women who achieve pregnancy through IVF require an increase in the L-T4 dose during gestation (185). This is a similar situation to hypothyroid pregnant women not having IFV (vide infra).

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. There is 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 (186). A recent study of 50 patients confirmed the link between thyroid function, forecast of conception and pregnancy, but noted that there is no recommendation on the TSH target level in patients undergoing assisted reproduction (187). 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.

Although a clear association exists between thyroid autoimmunity and pregnancy loss, systematic screening cannot be universally 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. However, many centers, in Europe and elsewhere, already routinely screen women with infertility and/or miscarriage for the presence of thyroid autoimmunity and dysfunction.

Preterm Birth

Preterm delivery (PTD) , that is birth occurring at or before 37 weeks gestation is a major cause of perinatal morbidity and mortality. It is reported to have an incidence of 12.7% (188) and an association with thyroid abnormalities was suggested (189). A subsequent review (190) concluded that autoimmune thyroid disease (positive thyroid antibodies in a euthyroid woman) is a risk factor for PTD and cited studies from Belgium, Pakistan and Italy in which PTD was observed in 16- 26.8% of TPOAb+ve women compared to 8-8.2% of antibody negative women ( all statistically significant). However, the incidence of PTD was only 4% in TPOAb+ve versus 3% in antibody negative women (p=ns) (191). Other groups have also failed to find an association between PTD and thyroid autoimmunity (192- 194). However, an increase in very preterm birth (before 34 weeks) was found in women who were TPOAb positive in the first trimester (192,195). A meta analysis of the studies defining PTD at 37 weeks showed an OR for the association of thyroid antibodies in 5 studies to be 2.07 [CI 1.17-3.68. p=0.01](159).A further meta-analysis(196) reviewed 11 prospective cohort studies involving 35, 467 participants and showed the combined RR of preterm delivery for pregnant women with thyroid antibodies compared with the reference group was 1.41 (95% CI 1.08-1.84, P=0.011). Other studies have also strengthened the association between PTD and thyroid autoimmunity (197-199). Although methodology and number of women studied varies in the different reports, current evidence suggests that the presence of TPO-Ab in pregnant women significantly increases the risk of preterm delivery. Further studies are required to evaluate other factors (eg ethnicity) associated with these findings. For example Interleukin-6 levels may also be an important factor (200). Thyroid disease is associated with systemic lupus erythematosus and pregnant patients with this disorder also have an increase in PTD (201).

Implications for Therapy

In the conditions referred to above the patients are all euthyroid. Although there may be a tendency in TPOAb+ve women to develop a raised TSH later on in pregnancy this only occurs in the minority. The Generaation R study indicated that hypothyroxinemia (RR about 3.5) as well as TPO-Antibody positivity (RR about 2.0) are risk factors for premature delivery (202) It has been suggested that L-thyroxine treatment may correct any slight deficiency in this clinical situation as well as influencing the systemic immune disturbance and the placental-decidual environment (159). Two prospective randomised trials by Negro and colleagues (176,203) support this view. In the first L-thyroxine (1mcg/kg/day)was given to women scheduled to have IVF treatment; this resulted in a 36% reduction in miscarriage rate. The later study used a mean L-T4 dose of 49.7mcg/day in women with positive antiTPOAb and noted a 75% reduction in miscarriage as well as a 69% reduction in pre-term births. More trials are awaited before a firm recommendation can be made. A systematic review (162) stated that for subclinical hypothyroidism and thyroid autoimmunity, evidence is insufficient to recommend treatment with levothyroxine. However a Cochrane review (204) stated that a reduction in preterm birth and a trend towards miscarriage with L-T4 was shown.The lack of prospective randomized controlled trials in this area of practice is currently impeding progress in high quality evidence based clinical decision making.

Clinical Epidemiology

The prevalence of overt and subclinical hypothyroidism in pregnancy is estimated at 0.3-0.5% and 2-3% (or even up to 5%) respectively (205,206). Endemic iodine deficiency is the most common cause of hypothyroidism seen in pregnant women worldwide. Even mild iodine deficiency can be associated with a high prevalence of thyroid autoimmunity in the first trimester (32), and inadequate iodine status has been accompanied by a high prevalence of hypothyroidism in pregnancy (207). However the main cause of hypothyroidism in iodine-replete populations is chronic autoimmune thyroiditis (208). Other causes include post-surgical, post-radioiodine ablation and hypothyroidism secondary to pituitary disease which, although rare, can include lymphocytic hypophysitis occurring during pregnancy or postpartum (209). (Table 14-6)

Table 14-6

Etiology and Diagnosis of Hypothyroidism in Pregnancy

Overt hypothyroidism in pregnancy may present classically but is oftentimes subtle and difficult to distinguish from the symptoms of normal pregnancy. A high index of suspicion is therefore required especially in women with a predisposition to thyroid disease such as a personal or family history of thyroid disease, the presence of goitre or the co-existence of other autoimmune disorders like type 1 diabetes.(210) which are all predictive factors of high risk of autoimmune thyroid disease. 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. An earlier review concluded that the overall prevalence of hypothyroidism was 2.2% to 3.4%, and the prevalence of thyroid antibodies ranged from 25% to 77% of hypothyroid pregnant women, with a mean prevalence of 46%. 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%) (211).

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 (212). Recently there have been a number of studies examining the relationship between ovarian reserve and thyroid autoimmunity (TA) using anti Mullerian hormone (AMH) as a marker for the former. Women with TA have a reduced ovarian follicular reserve (213). There is evidence that AMH levels are inversely correlated with TSH levels in infertile women of reproductive age (214). Although the probability of a poor response to controlled ovarian hyperstimulation (COH) is high and independent of autoimmune thyroid disease (AITD) in women with low serum AMH levels, in those women with good ovarian reserve (high AMH) the presence of AITD impairs the outcome of COH (215). In a large cross sectional retrospective study (216) it was found that a) serum thyroid hormone levels, anti-TPOAb and prevalence of subclinical hypothyroidism were no different in different ovarian reserve categories, b) a higher prevalence of subclinical and overt hypothyroidism was seen in women with a genetic cause for low ovarian reserve compared to those with unexplained cause. The relationship is clearly complex and further work is required.

Effect 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. Gestational hypothyroidism, and particularly subclinical hypothyroidism is not rare. Abalovich at al, showed that 34% of hypothyroid women became pregnant without thyroxine treatment: 11% of them had OH and 89% SCH (217).. When hypothyroid women become pregnant and maintain the pregnancy, they carry an increased risk for early and late obstetrical complications (Table 14-7). An analysis of 223,512 singleton pregnancies from a retrospective US cohort showed that , thyroid diseases were associated with obstetrical, labor, and delivery complications (218). Unfortunately these authors had no access to treatment details. Furthermore, in a study of 92 women on T4 replacement therapy the occurrence of maternal or fetal/neonatal complications could not be predicted by maternal TSH/fT4 through pregnancy, presence of thyroid autoimmunity or dose of LT4 replacement (219).

Table 14-7

Adverse Outcomes of Hypothyroidism

MOTHER

Infertility

Miscarriage

Preterm Delivery

Anemia in pregnancy

Preeclampsia

Abruptio placenta

Postpartum haemorrhage

BABY

Increased fetal death rate

Preterm birth

Intra Uterine Growth Retardation

Low birth weight

Increased neonatal respiratory distress

Impaired neurointellectual child development

Attention Deficit Hyperactivity Disorder

Autism

The frequency of these complications depends on whether they are associated with overt (high TSH associated with low FT4) or subclinical hypothyroidism (high TSH associated with FT4 within the reference range). With regard to fetal death rates Benhadi et al (154) noted that the risk of child loss increased with higher levels of maternal TSH although maternal FT4 concentrations and child loss were not associated. Ashoor et al (220-222) however, have observed that fetal loss was associated with both an increase in TSH and a decrement in FT4 although the presence of thyroid antibodies did not affect these results. They have also shown that impaired thyroid function may predispose to the development of late pre eclampsia (221) but they found no evidence of thyroid dysfunction or maternal thyroid antibodies to be related to preterm birth (222). A definitive study by Casey et al.(223) found that subclinical hypothyroidism in pregnancy has a relative risk of 1.8 for premature birth/low birth weight.Interestingly,maternal high-normal FT4 levels in early pregnancy were associated with lower birth weight and small for gestational age in the Generation R study of more than 4000 women (224). The continuous reciprocal relationship between maternal weight and FT4 has also been noted in the 2^nd trimester in more than 9000 women (225) An overview is given by Negro (226).

While the prevalence of hypothyroidism and subclinical hypothyroidism has been mentioned it should be noted that the state of isolated hypothyroxinemia (IH) occurs in around 2.5 to 10% depending on the definition employed (227). There has been controversy as to whether IH is a real entity and if so whether there are any adverse effects of the condition in gestation. The cause(s) of IH are not clear but iodine deficiency may be an important factor. IH does have adverse obstetric effects, although early studies of first trimester IH showed no adverse outcomes (228,229). Subsequent studies have documented an increase in preterm labour and macrosomia as well as gestational diabetes and increased placental abruption(230). Breech presentation,,larger fetal and infant head size and fetal distress have also been associated with IH (230-234). Despite these data guideline committees have concluded that there is not enough evidence to recommend L-T4 treatment in women with IH (13-15).

A review of the treatment of subclinical hypothyroidism SCH) in pregnancy concluded that while SCH is associated with multiple maternal and neonatal outcomes the value of L-T4 treatment remains uncertain (235). Nevertheless,adequate thyroxine treatment is critical to the outcome independent of the type of hypothyroidism (OH/SCH) A retrospective study of 150 pregnancies noted that adequate treatment of overt and SCH minimised the risks of abortion and premature delivery regardless of initial thyroid status,whereas inadequate therapy resulted in an increased rate of abortion and preterm deliveries (218) rate. A prospective randomised intervention trial also showed that even in euthyroid thyroid antibody positive pregnant women who were treated with thyroxine the rates of miscarriage and pre-term delivery were lower than euthyroid antibody positive women who did not receive thyroxine treatment (203). A retrospective study of women with SCH who were or were not prescribed L-T4 during pregnancy showed that the L-T4 group had fewer loss of pregnancies, and fewer low birth weight infants as well as better APGAR scores in the infants (236). From a practical point of view adherence to L-T4 therapy is critical and was noted to be low among 17% of women prescribed this drug in a large survey (237). Appropriate counselling is recommended.

Role of Thyroid Hormone During Fetal Brain Development

Thyroid hormones are major factors for the normal development of the brain. Extensive animal experiments reported by Teng’s group in China have shown neurodevelopmental impairment in subclinically hypothyroid rats due to alteration of the CREB signaling pathway (238) Marginal iodine deficiency affects dendritic spine development (239) and hypothyroxinemia also inhibits brain development (240,241). Hippocampal structure and function is affected in humans and rats resulting from thyroid hormone deficiency (242,243). The mechanisms of actions of thyroid hormones in the developing brain are mainly mediated through two ligand activated thyroid hormone receptor isoforms (244). Physiological amounts of free T4 are present in coelomic and amniotic fluids surrounding the developing embryo already in first trimester. Also, specific nuclear receptors are present in fetal brain as early as ~8 weeks post-conception (245). It is known that thyroid hormone deficiency may cause severe neurological disorders resulting from the deficit of neuronal cell differentiation and migration, axonal and dendritic outgrowth, myelin formation and synaptogenesis (246). This is the situation well documented in iodine deficient areas where the maternal circulating thyroxine concentrations are too low to provide adequate fetal levels particularly in the first trimester. Even in an iodine sufficient area maternal thyroid dysfunction (hypothyroidism, subclinical hypothyroidism or hypothyroxinemia) during pregnancy results in neuro-intellectual impairment of the child; hence maternal thyroid hormones are required through gestation for proper brain development and specific effects will depend on when maternal hormone deficiency occurs during pregnancy (247) The neurobiology of fetal brain development depends on many factors including the availability of thyroxine (T4) delivery to the fetal neurones (248) . There is also an important role for the thyroid hormone transporters in one or more of these processes (249). While MCT8 facilitates thyroid hormone transport to the neurone, OATP1C1 appears to be related to thyroid hormone transport into the astrocyte. At this stage it favours the transport of T4 more than T3 but as the deiodinase II is within the astrocyte this enables conversion to occur and then allows T3 to be transferred into the neurone. Other thyroid hormone transporters are probably regulating thyroid hormone transport into the oligodendrocyte. These processes depend on maternal iodide supply, maternal T4 synthesis, maternal T4 placental transport and the conversion of T4 to T3 in the fetus by the Type II deiodinase. The discovery that children born with the Allan-Herndon-Dudely syndrome have a mutation in the thyroid transporter monocarboxylate 8 (MCT8) (250 )has accentuated the interest in many of the transporters (251).Thyroid hormone receptor development in brain occurs very early in gestation, certainly before the fetal thyroid begins to function which is around sixteen to eighteen weeks (5). In early gestation thyroid hormone effects on genes related to neurodevelopment, for example, myelin, can be recorded.

Clinical Studies on the Role of Maternal Hypothyroidism for the Psycho-Neurological Outcome in the Progeny

Man et al(252) first noted 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 .

Impaired intellectual development has been reported in children born to women with non-iodine deficient hypothyroidism during pregnancy (253-255) as well as in children from hypothyroxinemic mothers (256- 261). Attention deficit disorder (262,263), autistic symptoms in offspring (264) and schizophrenia in later life (265) have been associated with maternal hypothyroxinemia. Attention deficit disorder was previously noted in offspring from mothers with thyroid autoimmunity (266). Children from mothers with anti thyroid peroxidase antibodies have been found to have intellectual impairment in early infancy (267) and a reduced childhood cognitive performance at age 4 and 7 and sensineural hearing loss at both ages (268).. Other studies have also shown suboptimal development in children exposed to hypothyroidism during pregnancy (269-271). If maternal T4 concentrations are corrected by the 20^th week (272) or prior to the 3^rd trimester (273,274) many of these adverse effects can be prevented..In addition, isolated hypothyroxinemia in the 2^nd trimester is not associated with impaired cognitive, language and motor scores at age 2 (275). These studies emphasise the temporal nature of fetal brain development (276) and underpin the notion that women should not have an abortion if hypothyroidism is found and treated in the first trimester The seminal study of Haddow et al (253) is worthy of further comment. They found that the full IQ scores of children whose mothers had a high TSH during gestation were 7 points lower than controls (p<0.005) and that 19% of them had scores of less than 85 compared to 5% of controls (p<0.007). However there was no IQ decrement noted in the prospective double blind randomized controlled antenatal thyroid screening study (CATS) study in children of both hypothyroxinemic and high TSH mothers studied at 3 years of age who received levothyroxine therapy during pregnancy compared to children whose mothers were not treated with levothyroxine (276). As mentioned above it is possible that the timing of thyroxine administration in gestation is an important factor (241).Indeed, a more extensive replication of the CATS study has reported no difference in IQ measurements in children up to the age of 5 whose mothers received or did not receive L-T4 during gestation, but the drug was not commenced till late in the 2^nd trimester (277). In a Chinese prospective population-based development study of 1017 women with singleton pregnancies clinical hypothyroidism was associated with increased fetal loss, low birth weight, and congenital circulation system malformations. Subclinical hypothyroidism was associated with increased fetal distress, preterm delivery, poor vision development, and neurodevelopmental delay. Isolated hypothyroxinemia was related to fetal distress, small for gestational age, and musculoskeletal malformations as well as spontaneous abortion (234). An important association study from the population based prospective study from Rotterdam (Generation R), which included MRI scans on the children, reported that maternal FT4 showed an inverted U shaped association with child IQ, child grey matter volume and cortex volume(278). This suggests that optimal T4 concentrations during gestation might require to be in a narrower range than previously thought. Brain morphology studies have also shown abnormal corpus callosum development in children born to women treated for hypothyroidism(279) and this maternal condition may also contribute to abnormal cortical morphology in the offspring (280). Maternal and/ neonatal thyroid function at delivery in children born at or over 37 weeks' gestation was not associated with impaired neurodevelopment at 5.5 years (281) although. lower levels of cord T4 were associated with increments in the McCarthy scales at this age. In premature infants (<34 weeks gestation) higher maternal levels of TSH at delivery were associated with significantly lower scores on the general cognitive index at 5.5 yr.(282)The neurodevelopmental impairment is similar to that seen in iodine deficient areas (see chapter on iodine deficiency) and implies that iodine status should be normalised in regions of deficiency. However, much of the USA and parts of Europe are not iodine deficient which raises the question of routine screening of thyroid function during early pregnancy or even at preconception which will be discussed below. In summary, the current weight of evidence suggests that hypothyroidism and subclinical hypothyroidism and hypothyroxinemia all have an adverse effect on neurodevelopmental outcome in the progeny. It is however the case that not all the evidence shows this and much of the evidence relates to association studies, Despite this there is a reasonable case for treatment of the woman with subclinical hypothyroidism in pregnancy to prevent these outcomes. However,treatment should be carefully monitored.

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.

A number of studies have indicated that during pregnancy thyroxine requirements increase during gestation (283-286). The increase is due to 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(208). . 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. In women not receiving T4 who may have risk factors for thyroid disease (eg positive family history or other autoimmune disorder) thyroid function should be measured pre conception. If the TSH is less than 2.5mIU/L no action is required. If it is more than 3.5mIU/L thyroxine therapy may be indicated, especially if thyroid antibodies are present. If TSH is between 2.5 and 3.5mIU/L it would be prudent to check again in 4 weeks if possible. 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 mg/kg bw/day (208,287)

Women who already take thyroxine before pregnancy usually need to increase their daily dosage by 30-50%, on average, above preconception dosage; appropriate dose increments must be made once pregnancy is confirmed t The preconception thyroxine dose should be adjusted aiming to maintain serum TSH near the low-normal range (288) which should be within the trimester specific reference range ( ie approx. 2.5 mIU/L) It has been suggested that if SCH is newly diagnosed in pregnancy a T4 dose of 1.20µg/kg/day is appropriate to achieve a TSH less than 4.2 mU/L(289).

In general women who receive T4 because of previous ablative treatment (eg for thyroid cancer) require a greater increase than those receiving the drug because of Hashimoto’s thyroiditis where there still may be some reserve thyroid tissue. Therefore patients with Hashimoto’s disease require a lesser increase in T4 dose. Before pregnancy thyroid function should be checked and T4 dose adjusted to achieve a serum TSH of at least less than 2.5mIU/L. Indeed, a retrospective study has suggested that in women on T4 for hypothyroidism who are planning to become pregnant should have TSH levels not greater than about 1.2mIU/L (290) although the guidelines are not so stringent in their recommendations (10-15). The woman should be advised to increase the dose of T4 by 30-50% once pregnancy is confirmed. A convenient method for achieving this for some women would be to take 2 extra tablets of T4 per week (284). Thyroid function (T4 and TSH) should then be checked every 4 weeks as dose requirements may change during the course of gestation. It has also been suggested that The increment in thyroxine can be based on the initial degree of TSH elevation; women with a serum TSH between 5-10 mU/L, the average increment in T4 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 (208).. The aim should be to keep the TSH around 2.5mIU/L or less remembering of course that TSH levels are difficult to interpret in the first trimester because of rising hCG concentrations. In the postpartum period most women should take their prepregnancy dose of T4. However some women with Hashimoto’s thyroiditis may require more than the pre-pregnancy dose because of possible postpartum progression of autoimmune thyroiditis (286). The question of compliance with therapy and the efforts of the physician to maintain the appropriate levels of thyroid hormone are important considerations particularly in the context of pregnancy (237). In 389 women, in the USA (185) 43% of serum TSH levels measured in 1st trimester were at or above 2.5 mU/L; In 2nd trimester, 33% of serum TSH measurements were at or above 3.0 mU/L (291). Even when the upper limit of TSH was defined as a serum TSH value above the 98th percentile of normal, 20% of values in 1st trimester and 23% in 2nd trimester were above this limit. In the UK , even in 18-45 year old pregnant women already on L-Thyroxine ,46% had a TSH level greater than 2.5 mU/L (292). These data suggest that the optimum care of pregnant women on L-thyroxine is not present despite evidence for its effect in reducing preterm birth and miscarriage (290,292). American Endocrine Society Guidelines recommend that as the potential benefits outweigh the the potential risks, women with SCH should receive T4 treatment (14,15). Women with autoimmunity (ie positive thyroid antibodies) should be carefully monitored during gestation as there is a tendency for a rise in TSH. If this occurs T4 therapy should be given.

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. Nonspecific 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 14-8). 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.

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 (297,298). 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 (299). 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

Prepregnancy Counseling

Prepregnancy counseling plays a very important role in the care of young women with Graves’ disease. All women of childbearing age affected with Graves’ hyperthyroidism should be strongly advised to seek contraception counseling, in order to avoid pregnancy while hyperthyroid (2,295). A discussion of the different hyperthyroid therapeutic choices is important for those women planning a pregnancy: ablative therapy, by 131I or surgery, or medical therapy. Before commencing specific treatment for a woman with GH in pregnancy it is essential to provide appropriate counselling advice [300). Risks to mother, fetus, and neonate from untreated GH during gestation are compelling reasons for recommending preconception counselling (PC). PC should include discussion as to the optimum treatment of GH in women wishing to become pregnant

1. If ablative therapy is chosen the following recommendations are suggested::
2. Pregnancy test prior to ablation,
3. Delay of conception on average of 6 months following therapy in order to adjust LT4 doses to target values for pregnancy (serum TSH 0.3-2.5).
4. Determination of TSH-receptor antibody (TRAb); the gradual disappearance from the circulation post therapy depends on the type of treatment chosen; following thyroidectomy there is a gradual disappearance of TRAb titers, while following 131I therapy there is an increase in TRAb titers that may last for 12 months followed by a gradual fall in titers (301). Therefore, in patients with high TRAb titers surgery appears to be the therapy of choice in women contemplating pregnancy (302).
5. B) For women on antithyroid drugs the following discussion with the patient and her family is recommended:
6. a) If still in need to ATD for more than 2 years, the possibilities of remission during pregnancy are very low, the patient, most likely, will need ATD therapy through pregnancy (see section below on management of Graves’ disease in pregnancy).
7. b) PTU may induce liver toxicity with potential liver failure requiring liver transplantation; therefore recommendations by the American Thyroid Association (13) limited the use of PTU to those patients allergic to MMI, in the treatment of thyroid storm and in the first trimester of pregnancy because of the rare instances of methimazole embryopathy. In a woman on MMI therapy at the time of conception or planning a pregnancy it is advisable to switch to PTU if it is deemed that ATD are required at that time and resume MMI after the first trimester.
8. c) Close follow-up throughout the pregnancy for frequent blood tests and adjustment of ATD dose, since the need for dose adjustments is common.
9. d) Possibility of disease aggravation in the first trimester and recurrence in the postpartum period, due to postpartum thyroiditis or recurrence of Graves’ (303).
10. e) Recommendations regarding breastfeeding while on ATDs.
11. f) TRAb determination for prediction of potential fetal or neonatal complications

Breast Feeding in Mothers with Treated Graves’ Disease

Lactation during ATD therapy has been discussed (351,). PTU and MMI are secreted in human milk, although PTU less so because of more extensive binding to albumin. With moderate doses of MMI or PTU (MMI: <20 mg/d; PTU: <250-300 mg/d), the risk to the infant is practically negligible.. The drug should be taken by the mother after a feeding but there is no need to monitor infant thyroid function. There is also a possibility that allergic reactions associated with ATD (agranulocytosis or rash) may occur in the infant. Wide experience has confirmed that the use of ATD in lactatin mothers does not pose a risk to the neonate and appears to be safe.

TSH Receptor Mutations Hypersensitive to hCG

The thyrocyte may be a passive bystander of abnormal thyrotropic activity of hCG in GTT, or it may play an active role in its response to hCG through variable degrees of sensitivity of the TSH receptor. A woman with recurrent gestational hyperthyroidism was reported (122) who, after two miscarriages, presented with overt hyperthyroidism and hyperemesis early in pregnancy,. 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, mistaken for 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. This finding remained unique until the same group described another case in 2016 (123). It is possible that some women who develop GTT may have an abnormality at the level of the TSH receptor, but perhaps not the same mutation as described (see Figure 14-14).

Figure14- 14

TSH receptor mutation, with a Lysine to Arginine mutation in position 183 of the ecto-domain. 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 122).

Thyroid Nodule Growth During Pregnancy

Thyroid nodules can be detected in up to 10% of pregnant women. In an iodine deficient area there was no correlation between pregnancy and nodular thyroid disease (365). In a Chinese population pregnancy is associated with an increase in preexisting thyroid nodules as well as new thyroid nodule formation (366). In a retrospective study from the California Cancer Registry from 1991 to 1999, 129 cases of thyroid cancer were diagnosed during pregnancy: 3.3/100,000 diagnosed before pregnancy; 0.3/100,000 at the time of delivery and 10.8/100,000 within one year after delivery (367).

Diagnostic Evaluation and Management of a Thyroid Nodule in Pregnancy

Fine needle aspiration biopsy is the first investigation of choice and in one report yielded a malignancy/suspicious result in 35%. (368). In the presence of a single thyroid nodule detected on physical examination, or a dominant nodule in a multinodular gland, confirmed by ultrasonography, the following approach is suggested :

a) solid lesion <1cm, follow up in the postpartum;

b) nodules >1-1.5 cm, should be considered for FNA if there are suspicious findings on ultrasound,

c) in the presence of tracheal obstruction, immediate surgery;

d) if the FNA is diagnostic of malignancy or it is a suspicious lesion, some authors recommend that surgery may be postponed until after delivery, unless there are lymph node metastases or the lesion is a large primary or there is extensive lymph node involvement in a medullary cancer,

e) surgery and FNAB could both be postponed until after delivery with probable safety,

f) a woman with a malignant lesion or rapid growth should be offered surgery in the second trimester of gestation;

g) Some authors recommend that women with follicular lesions or early stage papillary carcinoma may postpone the surgery until postpartum, since these lesions are not expected to progress rapidly (369,370).

In a retrospective study of 61 women pregnant at the time of the diagnosis of differentiated thyroid carcinoma (papillary cancer in 87%, follicular cancer 13%) 14 were operated on during pregnancy, the other 47 women undergoing surgery 1 to 84 months after delivery (371). The outcome was compared with a group of 598 nonpregnant women matched for age and similar follow up (median 22.4 years and 19.5 years respectively). Treatment and outcome were similar in those operated in the postpartum period. It was concluded that both diagnostic studies and initial therapy might be delayed until after delivery in most patients. Cancer registry data compared disease-related survival in 6505 women diagnosed with thyroid cancer during pregnancy or 1 year post delivery and noted no significant difference in outcome up to 11 years compared to an age-matched non-pregnant cohort (372). The impact of pregnancy on thyroid cancer had been considered to be minimal in that there is no difference in rates of metastases or recurrence compared to non-pregnant women with the same disease.

However, an Italian study of 123 women with differentiated thyroid cancer in relation to pregnancy concluded that pregnancy had a negative impact on the outcome, by showing a poorer prognosis compared to those women diagnosed in nongravid periods (373). The role of estrogen and estrogen receptor status in this regard is still not clear as there are data showing a proliferative effect on thyroid cancer cell lines(374) but there are other reports of estrogen only stimulating adenomatous tissue but not neoplastic thyroid (375). In addition recent studies on the effect of pregnancy on prognosis of differentiated thyroid cancer (DTC) have stated that persistence /recurrence of DTC is significantly higher in pregnant patients (376) and that pregnancy was associated with increase in size of papillary microcarcinoma (377), More studies are required on follow up and mechanisms for these observations.

Pregnancy and Co-existing Thyroid Malignancy

Whether women already treated for thyroid malignancy should become pregnant is of concern, but current evidence suggests that treated differentiated thyroid cancer without evidence of residual disease should not inhibit an intended pregnancy. A meta analysis of the association of thyroid carcinoma with pregnancy concluded that multiple pregnancies and a <5 year interval were indetified as high risk factors for thyroid carcinoma but thyroid carcinoma during pregnancy was not associated with a significant risk of lymphatic and distant metastases (378). In a retrospective analysis on 36 women who became pregnant a median of 4.3 years after initial therapy for differentiated thyroid carcinoma, and were evaluated a median of 4 months after delivery (0.1-1.7 years), total thyroidectomy was performed in 80% and lobectomy in 20% (379). From the clinical progression and serum thyroglobulin (Tg) values it was concluded that pregnancy “is probably a mild stimulus to cancer growth as evidence by minor disease progression in some patients with known structural disease before pregnancy”. Hirsch et al (380) evaluated 63 consecutive women (90 births), followed from 1992 to 2009 who had delivered at least once after total thyroidectomy plus 131-Iodine (in 58 of them) for papillary thyroid cancer. Serum thyroglobulin (Tg) values and neck ultrasound were compared before and after pregnancy. Six women out of the 63 showed disease progression during the first pregnancy and two had disease progression only during the second pregnancy. Serum TSH levels during pregnancy correlated with disease persistence before pregnancy and disease progression during pregnancy. An interesting finding was that a non-suppressed TSH level during pregnancy did not stimulate disease progression during pregnancy; They concluded that pregnancy does not cause thyroid cancer recurrence in PTC survivors who have no structural or biochemical evidence of disease persistence at the time of conception. A study of 24 patients with papillary cancer suggested that PTC during pregnancy may be more locoregionally aggressive but no difference in survival or recurrence was demonstrated compared to non pregnant women (381). The conclusion from these studies indicate no progression of the disease in women free of disease before pregnancy, however there is a possibility of progression in those patients with evidence of residual cancer at the time of conception. Further studies are needed before a firm recommendation could be offered to patients

In patients who are clinically and biochemically free of disease but who present with a high risk tumor, TSH suppression should be maintained with serum TSH levels between 0.1 – 0.5 mU/L. In low-risk patients free of disease, TSH may be kept within the low normal range (0.3–1.5 mU/L). Finally, in patients who have not undergone remnant ablation, who are clinically free of disease and have undetectable suppressed serum Tg and normal neck US, the serum TSH may be allowed to remain in the low normal range (0.3–1.5 mU/L) (371). The recent ATA guidelines(13) suggest that PTC detected in early pregnancy should be monitored sonographically. If it grows substantially before 24-26 weeks gestation, or if cytologically malignant cervical lymph nodes are present, surgery should be considered during pregnancy. However, if the disease remains stable by midgestation, or if it is diagnosed in the second half of pregnancy, surgery may be deferred until after delivery.The impact of pregnancy on women with newly-diagnosed medullary carcinoma or anaplastic cancer is unknown. However, a delay in treatment is likely to adversely impact outcome. Therefore, surgery should be strongly considered, following assessment of all clinical factors.

Effect of Previous 131 Iodine Therapy

Previous 131I therapy does not result in demonstrable adverse events in subsequent pregnancies (382). One of the most common concerns in young people, male and female, is the potential side effects on future fertility and pregnancies following Iodine 131 therapy, both for Graves’ therapy and thyroid cancer. The majority of studies (383-385) concluded that in young men, following 131Iodine doses of up to 3.7 GBq, serum FSH and LH increases with some oligospermia, with normalization within 18 months following treatment. There are few cases of permanent damage, related to patient age, therefore it is recommended to perform a semen analysis before treatment. The risk of testicular dysfunction is increased after repeated or high cumulative radioiodine activity (386). No effects on the progeny have been reported. The effect on women is very consistent in the many reported series. Women may have irregular menses in the first twelve months following therapy, with restitution of normal cycling and fertility thereafter. In a review of 54 studies (387) there was no increase in miscarriages, congenital malformations, or prematurity compared to previous treatment. Early onset of menopause has been reported (387). Overall doses up to 3.7 GBq resulted only in transient menstrual cycle abnormalities lasting up to one year, but no permanent ovarian failure. Although there are no specific studies assessing the risk of pregnancies within 12 months of 131Iodine treatment, the overall consensus by experts in the field is to postpone pregnancy for one year after ablation therapy. The importance of achieving a serum TSH within target should be emphasized. Determination of serum hCG in addition to the pregnancy test on the day of radioactive therapy is recommended, since several cases of false negative pregnancy tests have been reported.

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.

POSTPARTUM GRAVES’ DISEASE

Individual patients at high risk of postpartum onset of Graves' disease can be found in early pregnancy by the detection of TRAb. Up to 40% of women with Graves’ hyperthyroidism have been found to occur after a recent pregnancy (390) and The PP period is significantly associated with a relapse of hyperthyroidism in GD patients being in remission after ATD (391).

It is important to differentiate postpartum Graves' disease with accompanying hyperthyroidism from the other causes of postpartum hyperthyroidism. The presence of circulating TRAb , radioiodine uptake, together with clinical examination and thyroid scintiscanning will usually resolve any diagnostic difficulty. A combination of positive TRAb and high thyroid blood flow suggests the presence of Graves’ disease (392). Spectral Doppler sonography may also be useful at this time (393). However silent thyroiditis (i.e. postpartum thyroiditis) commonly develops concomitantly with the activation of Graves’ disease and may delay or mask the development of Graves’ hyperthyroidism .The serum thyroglobulin concentration, which is raised in postpartum destructive thyroiditis with hyperthyroidism, has also been shown to be useful for the differentiation of this condition from Graves’ hyperthyroidism following delivery. Therapy of postpartum Graves’ hyperthyroidism should be carried out by the usual methods remembering that radioiodine is contraindicated during breast feeding. In addition, radiation safety requirements may make it very difficult for the mother to care for her new born child. Ideally another carer should look after the child for at least a week if an activity of 400-600 MBq (app. 10-16 mci) is administered. Alternatively the patient may be treated with antithyroid drugs at this stage. Clearly, prevention of postpartum patients Graves’ hyperthyroidism may be achieved by adequate treatment of the condition before the onset of gestation (394). Screening for TRAb during pregnancy may detect patients at risk of postpartum relapse

Incidence

A variable incidence (from 3-17%) has been reported worldwide because of wide variations in the number of women studied, the frequency of thyroid assessment postpartum, diagnostic criteria employed and differences in hormone assay methodology. However there is a general consensus that the disease occurs in 5-9% of unselected postpartum women. Women with Type 1 diabetes have a three-fold incidence of PPT compared to non-diabetics. In these cases there is a strong association with thyroid antibodies. PPT is also more likely to occur in women who has had a previous episode.

Clinical Spectrum

PPTD is a destructive thyroiditis characterized by transient hyperthyroidism (median time of onset 13 weeks) and/or hypothyroidism (median time of onset 19 weeks) which may occur up to 9 months following delivery (400). The distribution of clinical presentation is approximately 19% hyperthyroid alone, 49% hypothyroid alone and the remaining 32% hyper followed by hypothyroidism. Although the clinical manifestations of the hyperthyroid state are not usually severe in PPT, lack of energy and irritability are particularly prominent even in antibody +ve women who do not develop thyroid dysfunction. In contrast the symptomatology of the hypothyroid phase may be profound. Raised levels of circulating thyroid peroxidase autoantibody (TPOAb) are detected in 10% of pregnant women at 16 weeks Of these, 50% develop PPTD during the first six months of the postpartum period (401) Permanent hypothyroidism is reported in as many as 30% of these cases after 3 years, and in 50 % at 7 - 10 years .An association with depression has been observed with PPTD (402); depression is also associated with thyroid antibody positive women irrespective of thyroid status (403,404). However, a study in an Australian population found no association between PPTD or thyroid antibody status with depression (405). TPOAb positivity has also been associated with dysphoric mood during and after pregnancy (406).

Diagnosis

Hyperthyroidism in the postpartum period may be due to a recurrence or the development of new Graves' disease or to the hyperthyroid phase of postpartum thyroiditis. Symptoms of hyperthyroidism are much more evident in Graves' disease .As postpartum hyperthyroidism is a destructive process radioiodine uptake will be very low at early and late times after isotope administration. TSH receptor antibodies are not seen unless there is coexisting Graves' disease. Hyperthyroidism due to postpartum thyroiditis is diagnosed by a suppressed TSH together with an elevated FT4 or FT3, or elevated FT3 and FT4, with either set of criteria occurring on more than one occasion. A report (407) of PPT with hyperthyroidism in a patient with thyroid hormone resistance noted the suppression of TSH in this state which is unusual in RTH. If possible a normal range of thyroid hormone concentrations should be derived in the postpartum period as they fall into a narrower range than the general population. Antibodies to thyroxine and T3, which may occur in autoimmune thyroid disease, may cause confusion in diagnosis but they are infrequent.

Hypothyroidism in the postpartum period is diagnosed when either TSH >3.6 mU/L together with FT4<8 pmol/l or FT3 <4.2 pmol/l or TSH 10mU/l on one or more occasion is present. The most frequent symptoms have been found to be lack of energy, aches and pains, poor memory, dry skin and cold intolerance. Thyroid ultrasonography has demonstrated diffuse or multifocal echogenicity reflecting the abnormal thyroid morphology and consistent with the known lymphocytic infiltration of the thyroid .The destructive nature of the thyroiditis is also shown by the increase in urinary iodine excretion in the hyperthyroid as well as the hypothyroid phase of the syndrome. In addition there is evidence that an early rise in serum thyroglobulin (a further indicator of thyroid destruction) may help in the identification of those women at risk of PPT.

Management of PPT

The hyperthyroid phase is relatively asymptomatic and usually requires no specific therapy. If symptoms of tachycardia and palpitations are troublesome of if other symptoms of hyperthyroidism such as sweating or anxiety are present then beta adrenoreceptor blocking agents may be used. Propanolol is the drug of choice but if nightmares develop a more cardioselective β blocker may be used. If this class of drug is contraindicated verapamil may be effective for cardiac symptoms. Antithyroid drugs are not indicated as the condition is a destructive thyroiditis. In contrast, patients experience persistent and troublesome symptoms related to the hypothyroid period and treatment with L-Thyroxine should be given starting with 0.1mg per day increasing as necessary. At this stage it will not be clear whether the patient has developed transient or permanent hypothyroidism. In this instance it is reasonable to treat with thyroxine for one year and then review the patient to determine the thyroxine requirement. This will normally mean that the patient should stop the therapy for 4-6 weeks and then have a thyroid function test. Patients who have been known to have transient thyroid dysfunction postpartum should be checked at least annually as 50% of them will develop hypothyroidism after 7 years. This is in contrast to TPOAb +ve women who have not experienced any thyroid dysfunction postpartum whose rate of hypothyroidism at 7 years follow up is only 5%. Clearly these patients require less intensive surveillance.

Follow Up and Course of the Syndrome

While the hyperthyroidism of PPT always resolves several long term studies of the hypothyroid phase have documented persistence of hypothyroidism in 20-30% of cases (397). Follow-up assessment of antiTPO positive women (at 16 weeks gestation) 9 years later has shown that the rate of development of hypothyroidism was significantly greater (48% vs 8% ) in those who had had PPT compared to those who were euthyroid antibody positive (408).. Recurrence of transient PPT has been observed by several workers and there is a 70% chance of developing recurrent PPT after a first attack and a 25% risk even if the woman was only anti- TPO positive without thyroid dysfunction during the first postpartum period.

Evidence for Intervention in High Risk Clinical Situations

The strength of evidence relating maternal hypothyroidism to low IQ in children suggests strongly that screening thyroid function in early gestation with l-thyroxine intervention in appropriate women would be beneficial. In addition there is evidence that such a strategy would be cost-effective. A study by Thung et al (418) compared the cost effectiveness of no screening versus routine screening for subclinical hypothyroidism in pregnancy.. The decision model demonstrated a saving of approximately $8.3 million per 100,000 women screened with an increment of 589.3 quality adjusted life years. Similar results were obtained by Dosiu et al (419) using a different screening model.

The lack of sufficient class A evidence has added to the controversy. Recent studies of targeted screening have concluded that targeted screening is unsatisfactory and that the data support the case for universal screening although more studies are required (420-422). The recommendation for universal screening has been made for pregnant women in Egypt (423), and pregnant women in China (424,425). An Asian survey found variable practice in relation to screening (426). Meanwhile other workers have recommended against screening (427,428). A recent opinion stated that testing maternal TSH as part of first trimester screening does not predict adverse pregnancy outcomes because mainly mild abnormalities in thyroid function are detected (429,430).

Several organisations have issued guidelines on whether to adopt a screening strategy for thyroid function in early pregnancy (11-15), the latest being the revised version of The American Thyroid Association guidelines (13). Generally, because of the lack of class A evidence (randomized controlled trial data) the recommendations from these guidelines) do not endorse universal screening. Instead, a targeted approach was suggested in specific clinical situations, although as noted below, this approach has limitations. The published Endocrine society of America guidelines (14) included a split recommendation, some members favoring universal screening, and others favoring targeted screening.A comparison of the 2 sets of recommendations is shown in table 14-12.

Table 14-12

Recommended patient profiles for targeted thyroid disease case finding in women seeking pregnancy, or newly pregnant:

ATA guidelines

History of thyroid dysfunction or prior thyroid surgery

Age >30 years

Symptoms of thyroid dysfunction or the presence of goiter

TPOAb positivity

Type 1 diabetes or other autoimmune disorders

History of miscarriage or preterm delivery

History of head or neck radiation

Family history of thyroid dysfunction

Morbid obesity (BMI ≥40 kg/m2)

Use of amiodarone or lithium, or recent administration of iodinated radiologic contrast

Infertility

Residing in an area of known moderate to severe iodine insufficiency

Endocrine Society Guidelines

Women over age 30 years ( ? Valid see 310a)

family history of autoimmune thyroid disease or hypothyroidism

goiter

thyroid antibodies, primarily thyroid peroxidase antibodies

symptoms or clinical signs suggestive of thyroid hypofunction

type 1 diabetes mellitus, or other autoimmune disorders

infertility

prior history of preterm delivery

prior therapeutic head or neck irradiation or prior thyroid surgery

currently receiving levothyroxine replacement

A comparison between the first ATA guidelines (12) and those of The Endocrine Society (14) concluded that the data available at that time are neither for or against universal screening (431).

Althoughtargeted screening might seem a reasonable approach in relation to economic and logistic factors, there has been accruing evidence that a substantial number of women with thyroid dysfunction would not be diagnosed in these circumstances. Vaidya (432) found that targeted testing of a previously defined high risk group who had a personal history of thyroid or other autoimmune disorders or a family history of thyroid disease (413 women) failed to detect 28% of pregnant women with a TSH>4.2mIU/L. Li et al (255) found that this strategy missed 36% of women with TSH>4.0mIU/L. Overall , targeted screening may miss 33-88% of women with a thyroid abnormality (420,423,424,432-435, ). For example, screening ‘low risk women’ identified 28% with thyroid dysfunction excluding those with just positive thyroid antibodies (420). The variability seen in these data may relate to different definitions of thyroid dysfunction and different ethnicity of the populations studied. A meta analysis performed by obstetricians in The Netherlands concluded that he overall lack of evidence precludes a recommendation for universal screening and is only justified in a research setting (162). Despite a lack of consensus among professional organisation many areas of the world are in fact performing routine screening (436-438).In the USA 74% of respondents at an ATA meeting advocated universal thyroid screening with TSH (439). To date there is an ongoing disussion relating to the evidence that levothyroxine treatment of pregnant women with subclinical hypothyroidism, isolated hypothyroxinemia, or thyroid autoimmunity is beneficial (439,,13,15). Therefore, there is ongoing debate regarding the need for universal screening for thyroid dysfunction during pregnancy . Efforts are still required to provide more high quality evidence to justify screening. There is some evidence that screening (with thyroxine intervention therapy) may at least prevent or reduce some obstetric complications associated with SCH in pregnancy (440,441). Meanwhile, optimal cooperation and communication between endocrinologists and obstetricians is also necessary.

Conclusion

The screening criteria for subclinical hypothyroidism in pregnancy are largely met. The condition is not rare and several retrospective studies imply adverse obstetric and child neurodevelopmental outcomes. However there are few prospective randomized trials to substantiate the benefit of screening and the CATS study did not show a benefit in child IQ at age 3 years (276). Nevertheless there seems to be a case for screening to prevent adverse obstetric outcomes. From the child cognitive function aspect there should be further studies where intervention is initiated early in the first trimester during the course of brain development. Unfortunately the recent NIH study reported in abstract indicated that recruitment of mothers was at least midway in the second trimester (277)

From the forgoing discussion this author believes that the lack of high quality clinical epidemiological evidence base probably does not justify universal screening at the present time. Other authors note that the data on the beneficial effects of treatment for subclinical hypothyroidism remain uncertain, but that the other established benefits justify universal screening at this time. However, it is likely that more evidence will be produced which may alter this view in the future. Other authors have suggested that screening may be worthwhile rather than searching for minor abnormalities in thyroid function tests (442) and that screening could be introduced on the premise that overt hypothyroidism is the target condition and that there is agreement with regard to treatment ( Meanwhile it must be admitted that screening is occurring round the world in a pragmatic fashion.