Management of hypo- and hyperthyroidism during pregnancy

Growth Hormone & IGF Research 13 (2003) S45–S54 www.elsevier.com/locate/ghir

Management of hypo- and hyperthyroidism during pregnancy Daniel Glinoer * Department of Internal Medicine, Thyroid Investigation Clinic, Universit
e Libre de Bruxelles, Centre Hospitalo-Universitaire Saint-Pierre, 322 Rue HAUTE, 1000 Brussels, Belgium

Abstract Pregnancy has profound effects on the regulation of thyroid function, and on thyroidal functional disorders, that need to be recognized, carefully assessed and correctly managed. Relative hypothyroxinemia and goitrogenesis may occur in healthy women who reside in areas with restricted iodine intake, strongly suggesting that pregnancy constitutes a stimulatory challenge for the thyroid. Overt thyroid dysfunction occurs in 1–2% of pregnant women, but mild forms of dysfunction (both hyper- and hypothyroidism) are probably more prevalent and frequently remain unrecognized. Alterations of maternal thyroid function have important implications for fetal and neonatal development. In recent years, particular attention has been drawn to the potential risks for the developing fetus due to maternal hypothyroxinemia during early gestation. Concerning hyperthyroidism, the two main causes of thyrotoxicosis in the pregnant state are GravesÕ disease and gestational transient thyrotoxicosis (GTT). The natural history of GravesÕ disease is altered during pregnancy, with a tendency for exacerbation during the first trimester, and amelioration during the second and third trimesters. The natural history of the disorder must be considered when treating patients, since antithyroid drugs cross the placenta and can directly affect fetal thyroid function. Algorithms to routinely screen pregnant women for thyroid dysfunction have been proposed in recent years, but these have not yet been implemented systematically, nor have they been the subject of cost-effectiveness analyses. Ó 2003 Elsevier Science Ltd. All rights reserved. Keywords: Pregnancy; Hypothyroidism; Hyperthyroidism; Hypothyroxinemia; GravesÕ disease

1. Introduction

2. Hypothyroidism

Pregnancy has profound effects on thyroid function and on the course of thyroid diseases, for instance in patients with preexisting autoimmune thyroid dysfunction (AITD). Since AITD is especially common in women and has a high prevalence during the child-bearing years, it is important to understand precisely both the expected changes in thyroid function tests that are associated with a pregnancy and how this condition may affect preexisting thyroiditis, hypothyroidism, and GravesÕ disease in these women. In this paper, the diagnostic and therapeutic aspects that must be kept in mind in the care of pregnant patients with thyroid disease are briefly reviewed.

2.1. Epidemiology and clinical implications

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When hypothyroidism does not result from the previous radical treatment of hyperthyroidism using radioiodine or surgery, the most common cause of primary hypothyroidism in women of child-bearing age is chronic autoimmune thyroiditis. This occurs in both goitrous and atrophic forms. Approximately 1–2% of patients who become pregnant are already receiving levothyroxine therapy for hypothyroidism. In two population-based studies (one retrospective and one prospective), the prevalence of elevated serum thyroidstimulating hormone (TSH) concentrations in the early part of gestation in women without apparent hypothyroidism represented 2–3% of apparently healthy, unselected pregnancies. The percentage of pregnant women with an abnormal serum TSH that has AITD is 40–60%, compared with a prevalence of only 7–11% of

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antibody-positive non-pregnant women in the same age range. A much rarer cause of hypothyroidism during pregnancy is that associated with the presence of TSH receptor-blocking antibodies. In such patients, hypothyroidism is presumably caused by interference in TSH to TSH-receptor interactions. Even though uncommon, the clinical significance of this problem during pregnancy is that thyroid-blocking antibodies may be transferred to the fetus and cause intrauterine or transient neonatal hypothyroidism [1–6]. Women with circulating thyroid autoantibodies have an increased rate of spontaneous abortions. This is not always the consequence of associated overt hypothyroidism, and presently it is still not clear what causal relationship exists between the two phenomena. The presence of thyroid immunity represents an independent marker of an at-risk pregnancy. Also, there is a known association between hypothyroidism and decreased fecundity which, in most instances, is primarily associated with ovulatory disturbances and not with miscarriage. For instance, women treated with thyroid hormone have a twofold increased risk of primary ovulatory infertility. When hypothyroid women do become pregnant, they also have an increased risk for obstetrical complications, including intrauterine fetal demise, gestational hypertension, placental abruption and a poorer perinatal outcome. Even though there are only a few reports on the outcome of pregnancy in women with untreated hypothyroidism, most available information indicates that adequate treatment with thyroid hormone greatly reduces the frequency of these abnormalities [7–12]. 2.2. Screening and diagnosis during pregnancy The diagnosis of hypothyroidism during pregnancy can be readily established by measuring serum free thyroxine (T4) and TSH. The total serum T4 should be increased by 4–5 lg/dl (50–60 nmol/L) in the pregnant state, whereas free T4 remains normal. The signs and symptoms of hypothyroidism are similar to those in the non-pregnant woman; however, they may be difficult to separate from nonspecific symptoms such as fatigue commonly associated with pregnancy. AITD is common in young women, and subclinical hypothyroidism often remains undiagnosed. Therefore, systematic screening for hypothyroidism during pregnancy is justified since obstetrical repercussions are associated with untreated hypothyroidism. Among the possible algorithms, the following schema has been proposed (Fig. 1). As a first step, serum TSH and thyroid antibodies are measured during early gestation (ideally, both thryoglobulin antibodies [TG-Ab] and thyroperoxidase antibodies [TPO-Ab]). However, if only one thyroid antibody can be assessed for economical reasons, TPO-Ab is preferable because it yields the best diagnostic score. We also now propose to include

Fig. 1. Stepwise algorithm for the systematic screening of autoimmune thyroid disorders (AITD) and thyroid underfunction during pregnancy, based on the determination of thyroperoxidase (TPO-Ab) and thyroglobulin (TG-Ab) autoantibodies, serum TSH and free T4 concentrations during early gestation. Adapted, with modifications, from [6]. Symbols: Ab), negative antibody titers; Ab+, positive antibody titers; GA, gestational age; L -T4: L -thyroxine; PP, postpartum.

measurement of free T4 in the algorithm. When serum TSH is above 4 mU/L (or free T4 below normal), irrespective of the presence (or absence) of thyroid antibodies, the patient should be suspected of having thyroid underfunction. Based on these results and the clinical assessment of the patient, levothyroxine should be given throughout pregnancy and thyroid function parameters monitored every trimester. These women should also be followed during the postpartum period. The second step in the algorithm concerns women with positive thyroid antibodies. We propose to base the medical response on the serum TSH levels during early pregnancy. When serum TSH is below 2 mU/L (this is most frequently associated with relatively low titers of thyroid antibodies), systematic treatment is not warranted, but serum TSH and free T4 should be monitored at the end of the second trimester. For women with thyroid antibodies and a serum TSH concentration still within the normal range, but between 2 and 4 mU/L during early gestation (this is most frequently associated with higher titers of thyroid antibodies), treatment with L -T4 should be considered. Serum TSH is down-regulated (under the influence of human chorionic gonadotropin [hCG]) during the first half of gestation, and the thyroid deficit in women with thyroid immunity tends to deteriorate as gestation progresses. Judgment should be based on free T4 levels; if low or low-normal for the gestational age, treatment with thyroxine may be justified. This treatment schema has been put into practice in collaboration with obstetricians; however, prospective studies are needed to assess the final clinical relevance of the proposed treatment plan. Even though there is not as yet direct evidence of an advantage in treating subclinically hypothyroid women during gestation, indirect arguments suggest that no harm can be done and that

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such treatment can only be beneficial for the patient and her unborn child [13–15]. 2.3. Therapeutic considerations In the newly diagnosed hypothyroid patient, a full replacement dose of L -T4 should be administered immediately (assuming there are no abnormalities in cardiac function). To rapidly normalize the T4 pool, L -T4 therapy may be administered for 2–3 days at a dose that is 2–3 times the estimated final replacement daily dose. This will result in a rapid normalization of the circulating T4 levels and a more prompt return to the euthyroid state. Several studies have now confirmed that thyroxine requirements in women with preexisting hypothyroidism increase during pregnancy (mean increment: 45%). There are several reasons for the increased dose requirement, which may vary in importance depending upon time of gestation. These include the estrogen-induced increased thyroxin-binding globulin (TBG) concentrations, increased tissue volume of distribution and increased placental T4 degradation and transport. The adjustment of levothyroxine dosage should be implemented as early as possible during gestation, specifically within the first trimester. If the pregnancy is planned, thyroid function tests should be obtained soon after the missed menstrual period. If serum TSH and free T4 are normal at that time, tests should be repeated at 8–12 and 20 weeks gestation, since the increase in hormone requirements may not become apparent until later. The magnitude of the increased requirement may, in part, depend upon the etiology of hypothyroidism. In women with a previous history of radioiodine ablation for hyperthyroidism, the mean dose increase is 50%, whereas in those with AITD (HashimotoÕs disease), the mean dose increase is 25%. It is important to emphasize that 25% of those patients with initial normal serum TSH levels in the first trimester and 37% of those with initial normal serum TSH levels in the second trimester will later require dosage increases. Women with subclinical hypothyroidism who are taking small doses of levothyroxine (less than replacement doses) before pregnancy may not systematically require a dosage increase during gestation (though they frequently do) as long as their glandular functional reserve is able to increase endogenous synthesis of thyroid hormone. After delivery, the L -T4 dose should progressively be reduced to its pregestational level and the TSH concentration rechecked at the postpartum visit (6–8 weeks). 2.4. Maternal hypothyroidism and neuro-psychointellectual fetal development In general, infants of hypothyroid mothers appear healthy, without evidence of thyroid dysfunction, pro-

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vided that no iodine deficiency has been present in utero. Obviously, severe maternal hypothyroidism during pregnancy raises concern about the potential long-lasting psycho-neurological consequences for the unborn child due to insufficient transplacental transfer of maternal thyroid hormones to the developing fetus during the first half of gestation, before the fetal thyroid gland becomes functional. The potential risks for fetal and neonatal repercussions of undisclosed thyroid underfunction (hypothyroxinemia) during pregnancy have become public knowledge following the publication of two important studies in 1999 (Haddow et al., Pop et al.) [16,17]. These studies have attracted the attention of the press and the medical community and further highlighted the complex relations that exist between maternal thyroid dysfunction during pregnancy and the possible consequences for the neuro-psychointellectual development of the fetus and child. Three important recently published review papers provide detailed information [18–20]. Contrary to past belief, an important new concept of thyroid function and regulation in the fetus is that thyroid hormones are transferred from the mother to the fetus, both before and after the onset of fetal thyroid function [21]. The architectural development of the fetal brain (neuronal multiplication, migration and organization) during the second trimester corresponds to a phase during which the supply of thyroid hormones to the growing fetus is almost exclusively of maternal origin. During the next phase of fetal brain development (glial cell multiplication, migration and myelinisation), which occurs in third trimester, the supply of thyroid hormones to the fetus is essentially of fetal origin. Therefore, while severe maternal hypothyroidism during the second trimester will result in irreversible neurologic deficits, maternal hypothyroxinemia occurring at later stages will result in less severe, and also partially reversible, fetal brain damage. Thus, the adequate functioning of both the maternal and fetal thyroid glands plays an important role in ensuring that the neuro-psychointellectual development progresses normally. When the maternal thyroid gland is functionally deficient (such as in autoimmune hypothyroidism), both the severity and the temporal occurrence of maternal underfunction drive the resulting consequences for an impaired fetal neuronal development. Clinical situations of this type may appear during early gestational stages (such as in the case of women with known but untreated or undertreated hypothyroidism) or may not be evident until later gestational stages. In 1999, Haddow et al. reported the results of a prospective investigation of the neuro-psychological development of children (aged 7–9 years) born to mothers diagnosed 8–10 years previously as having variable degrees of thyroid deficiency during pregnancy. Investigators recruited children born to 62 women with

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an abnormally elevated serum TSH at 17 weeks gestation (14 women had already received L -T4 during pregnancy). The study group consisted of the 62 children born to these mothers and a suitable control group of 124 children born to healthy, matched mothers. Neuropsychological testing included evaluation of performances in 15 tests relating to intelligence, attention, language, reading abilities, school performance and visual-motor performance. The children of the thyroiddeficient mothers performed less well on the neuropsychological tests performed. Differences in IQ scores were evident in the children of untreated hypothyroid mothers (on average, a 7-point difference; score of 100 versus 107). In contrast, the children born to hypothyroid mothers treated with thyroxine had IQs similar to control children. Another important finding was that 19% of the children born to untreated hypothyroid mothers had IQs below 86, compared with only 5% of control children. Finally, 77% of mothers had thyroid antibodies, hence confirming that chronic ‘‘asymptomatic’’ AITD was the most frequent underlying cause of thyroid underfunction (with a diminished functional reserve). The conclusion was that decreased intellectual and school performances can occur even if a pregnant womanÕs hypothyroidism is mild and asymptomatic. It is important to note that a majority of these women subsequently developed overt hypothyroidism, with a long median period of 5 years before the final diagnosis of definitive hypothyroidism was reached [16,22]. In a European study in 1999, Pop et al. investigated psychomotor development in 22 infants born to mothers with low-normal free T4 concentrations (<10.4 pmol/L) at 12 weeks gestation [17]. InfantsÕ development performances were evaluated at the age of 10 months, using the Bayley Psychomotor Developmental Index (PDI). The authors showed that these infants had a 7% negative difference in the PDI score, compared with the controls. The conclusion was that early maternal hypothyroxinemia represented a significant risk factor for impaired development during the first year of life [17]. In summary, recent studies have affirmed the belief that diminished maternal thyroid function during pregnancy – even when mild and considered subclinical (especially when present in early gestation) – may be associated with impaired normal brain development in offspring. Alterations of the neuro-psychointellectual outcome in offspring may result from a combination of factors related to perinatal hypothyroidism. The relationships between maternal and fetal thyroid functions are complex, both in physiological and disease conditions; therefore, no simplistic model can be applied to account for the variety of conditions and degrees of severity of developmental impairment that have been observed. Poor infant intellectual performances may ultimately result from the deleterious effects of maternal hypothyroidism alone, from impaired fetal thyroid

function alone, or from a combination of both. With regard to maternal hypothyroidism, the harmful effects of hypothyroxinemia on the development of fetal brain structures are most evident during the early stages of gestation. In addition, pediatric effects may be related to maternal hypothyroidism occurring during late gestation and probably also from hypothyroidism taking place (or persisting) during the postpartum period, presumably through indirect consequences related to the ‘‘less well-being’’ status, which is often characteristic of non-recognized hypothyroidism. The key finding from these recent studies is that altered neuro-psychointellectual development may occur in offspring, even in the presence of mild and perhaps only transient maternal hypothyroxinemia, and in the absence of detectable abnormalities of thyroid function in infants at birth. In most clinical circumstances where a woman with AITD has defective thyroid function, hypothyroxinemia is not restricted to the first trimester and hypothyroidism tends to worsen as gestation progresses, especially when left undiagnosed and un(der)treated. The fetus, therefore, may be deprived of adequate amounts of thyroid hormones, not only in early brain development stages, but also during later neurological maturation and development. Because of these effects, early detection and treatment of hypothyroxinemia is crucial. Regarding the causal relationship between maternal thyroid deficiency and the risk of altered neuro-psychological development, we have recently proposed that the issue can be viewed as ‘‘a coin with two sides’’. If one side represents the ‘‘hardware’’ part of the causal relationship, namely missed and/or abnormal neuronal connections having taken place during early development, the other ‘‘software’’ side of the coin corresponds to the indirect repercussions of undiagnosed or inadequately treated hypothyroidism during pregnancy on the motherÕs capability to raise her child in the most effective psychostimulating manner. Ultimately, any delay in diagnosing and treating maternal hypothyroxinemia may result in decreased intellectual development of the offspring (lower IQ), with the educational, socioeconomic and public health consequences that may be foreseen. Since hypothyroidism is not rare in women of child-bearing age, systematic screening for hypothyroidism is probably worthwhile during pregnancy. Practically, it is impossible to routinely screen populations before pregnancy starts (except in a minority of patients with a personal history of thyroid disorder, or a family history of AITD, or long standing infertility, etc). In our opinion, the regular screening for chronic autoimmune thyroiditis and the assessment of iodine nutritional status, followed by their correction and treatment, is beneficial for both the neurointellectual potentialities of the offspring as well as the health of the mothers. In addition, this practice will probably be cost effective, although we are aware that long-term studies will still be

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required to confirm this view. Many European medical centers have initiated similar detection, monitoring and patient management procedures, without waiting for institutional or governmental bodies to propose consensus guidelines. Finally, additional studies are needed to closely evaluate the causal relationship between maternal alterations of thyroid function during pregnancy and the potential detrimental neuro-developmental repercussions in offspring. In the mean time, as recently and wisely suggested by Smallridge and Ladenson, ‘‘physicians and obstetricians must do what they have to so often when evidence is incomplete: use their own judgment about the optimal management for their individual patients’’ [20].

3. Hyperthyroidism 3.1. Epidemiology and clinical implications Hyperthyroidism during pregnancy is much less common than hypothyroidism. It has been estimated indirectly that approximately 1–2 in 1000 pregnancies is complicated by hyperthyroidism. The causes of hyperthyroidism include ones evident in the general population, as well as others that occur only during pregnancy. Clinical entities such as toxic adenoma, multinodular toxic goiter, subacute or silent thyroiditis, iodideinduced thyrotoxicosis, and thyrotoxicosis factitia are extremely uncommon during pregnancy. Molar disease should always be considered and can potentially lead to severe thyrotoxicosis; however, uncomplicated hydatidiform mole is now easily diagnosed in the early stages of gestation, and therefore rarely leads to severe hyperthyroidism. The major cause of hyperthyroidism in women of child-bearing age is GravesÕ disease. In recent years, another cause has been characterized, resulting from the direct stimulation of the thyroid gland by human chorionic gonadotropin (hCG), which can induce a transient form of hyperthyroidism during the first half of gestation. This syndrome is referred to as gestational transient thyrotoxicosis (GTT), and it occurs more frequently, but usually less severely, than hyperthyroidism due to GravesÕ disease. GTT differs from GravesÕ disease in that it is not of autoimmune origin and the course, fetal risks, and management and follow-up of both entities are different (Fig. 2). The diagnosis of hyperthyroidism can readily be confirmed by appropriate and simple laboratory tests. Virtually all patients with significant clinical symptoms have a serum TSH <0.1 mU/L as well as concurrent elevations in serum free T4 and T3 levels. In the first trimester, serum TSH may be transiently suppressed in 10–20% of euthyroid women (<0.2 mU/L) at the time of peak hCG levels. Therefore, the degree and duration of

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Fig. 2. Three-step algorithm for the systematic screening of thyroid hyperfunction during pregnancy, based on the data available from screening for hypothyroidism. The first step allows for the diagnosis of unsuspected hyperthyroidism of autoimmune origin; the second step for the diagnosis of gestational transient thyrotoxicosis (GTT); the third step concerns the patients with GravesÕ disease (active or considered cured). Adapted, with modifications, from Glinoer [6]. Symbols: Ab), negative antibody titers; Ab+, positive antibody titers; L -T4, L -thyroxine; PP, postpartum; TSH, thyroid stimulating hormone; TSHR-Ab, TSH-receptor antibody titers; TPO-Ab, thyroperoxidase antibody; hCG, human chorionic gonadotropin.

TSH suppression during the first trimester must be considered in making the diagnosis. Since most patients with GravesÕ disease have positive tests for thyroid autoantibodies, antibody presence should alert the clinician to the possibility that autoimmune thyroid disease is the cause of symptoms evoking hyperthyroidism. 3.2. Graves’ disease in pregnancy Three clinical situations are important to consider: (1) women with active GravesÕ disease diagnosed before pregnancy who are receiving antithyroid drug (ATD) treatment; (2) women who are in remission or considered cured after prior treatment; and finally, (3) women in whom the diagnosis of GravesÕ disease has not been established before the onset of pregnancy, but who have TSH receptor antibodies (TSHR-Ab). An important concept is that maternal and fetal outcome is directly related to adequate control of hyperthyroidism. Several reports have identified important obstetrical consequences such as preeclampsia, fetal malformations, premature delivery and low infant birth weight when thyrotoxicosis remains uncontrolled (usually following poor compliance to therapy). For patients in whom the diagnosis is correctly made early in pregnancy and treatment is promptly started, the prognosis for both the mother and the offspring remains excellent. The overall goal of medical management is to keep the patient at a high euthyroid or borderline hyperthyroid level of thyroid function throughout pregnancy, using the lowest possible dose of ATD. Another consideration is that TSHR-Ab may remain elevated, even after prior

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thyroidectomy or thyroid ablation using radioiodine or the apparent cure of hyperthyroidism with ATD several years before pregnancy. The risk for fetal and neonatal hyperthyroidism is negligible in euthyroid women not currently receiving ATD treatment, but who had received antithyroid drugs previously for GravesÕ disease; therefore, systematic measurements of TSHR-Ab are not mandatory. For a euthyroid woman (with or without thyroid hormone substitution therapy) who has previously received radioiodine therapy or undergone thyroid surgery for GravesÕ disease, the risk for fetal and neonatal hyperthyroidism depends on the level of TSHR-Ab in the mother. As a result, antibodies should be measured early in pregnancy to evaluate this risk. For a pregnant woman who takes antithyroid drugs for active GravesÕ disease (assuming that therapy was started before or early during pregnancy),TSHR-Ab should be checked again in the last trimester. If the antibody titers have not substantially decreased during the second trimester, the possibility of fetal hyperthyroidism should be considered [23–28]. Hyperthyroidism due to GravesÕ disease usually tends to progressively improve during the course of gestation. Several reasons may help to explain this spontaneous improvement: (1) partial immunosuppression – characteristic of pregnancy – with a significant decrease in TSHR-Ab titers; (2) marked rise in serum TBG levels, which tends to reduce free T4 and T3 fractions; (3) obligatory iodine losses specific to pregnancy which may constitute, paradoxically, an advantage for pregnant patients with GravesÕ disease; and finally, (4) the suggestion that the balance between TSH-receptor antibody blocking and stimulating activities may be modified in favour of blocking autoantibodies. Pregnant patients with active GravesÕ disease should be treated exclusively with ATD, unless the severity of the condition justifies (exceptionally) a more radical approach by surgery, which is then preferably carried out during the second trimester. The dosage of ATD should be maintained at a minimum and the drugs discontinued as soon as possible (often after 4–6 months gestation). Combined administration of ATD and thyroxine to the mother to maintain euthyroidism in the fetus should be avoided since the transplacental passage of ATDs is high, while it is negligible for thyroid hormones. All ATDs cross the placenta and may, therefore, affect fetal thyroid function. The thiourea drugs, propylthiouracil (PTU), methimazole (MMI) and carbimazole (CMI, which is rapidly metabolized to MMI) have been compared with respect to their use during pregnancy. PTU is more water soluble and is therefore less well-transferred from maternal to fetal circulation as well as from the maternal circulation into breast milk. This has led to the recommendation that during pregnancy, PTU should be used in preference to MMI or CMI, unless a specific therapy is directed to also

suppress thyroid function in the fetus. However, MMI and CMI are commonly used during pregnancy in many countries where PTU is not commercially available without particular problems. As a result, we feel that the recommendation for sole use of PTU is not fully justified. Concerning the risks of fetal hypothyroidism induced by maternal treatment with ATD, most studies have concluded that there is little reason to choose PTU over MMI [29–32]. 3.3. Overall management guidelines: Graves’ disease during pregnancy [6] 1. Monitor pulse, weight gain, thyroid size, free T4 and T3 and TSH at monthly intervals. 2. Use the lowest doses of ATD that will maintain the patient in a mildly hyperthyroid state but not higher than 300 mg PTU (or 20 mg MMI). 3. Communicate regularly with the obstetrician, especially with respect to fetal pulse and growth. 4. Do not attempt to normalize serum TSH. Serum TSH concentrations between 0.1 and 0.4 mU/L are generally appropriate, but lower levels are acceptable if the patient is clinically satisfactory. 5. PTU is usually preferred to MMI, but both types of ATD can be used. 6. While even as little as 100–200 mg of PTU/day may affect fetal thyroid function, dosages as high as 300 mg PTU (20 mg MMI) have been used. Do not use iodides during pregnancy except to prepare patient for surgery. 7. Indications for surgery are: (a) requirements for high doses of PTU (>300 mg) or MMI (>20 mg) with inadequate control of clinical hyperthyroidism; (b) poor compliance with resulting clinical hyperthyroidism; or (c) the appearance of fetal hypothyroidism (retarded bone age, bradycardia) at ATD doses required for control of disease in the mother. 8. Usually the dose of ATD can be adjusted downward after the first trimester and often discontinued during the third trimester. 9. ATD will often need to be reinstituted or increased after delivery. GravesÕ disease during pregnancy can affect the fetus in several ways. First, when maternal TSHR-Ab are elevated during early gestation and the antibody titers have not substantially decreased during the second trimester, fetal (and neonatal) hyperthyroidism constitutes a real risk. This risk can be assessed by ultrasonographic data indicating the presence of a fetal goiter, tachycardia (>160 bpm), growth retardation, increased fetal motility or accelerated bone maturation. In selected cases, fetal cord blood sampling may be required for diagnosis or for monitoring therapy. If persistent fetal tachycardia is present, it is reasonable to initiate ATD therapy (200–400 mg PTU or 20 mg MMI) in the mother with

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thyroxine supplementation to maintain maternal euthyroidism when needed. Second, both the hyperthyroidism itself and the administration of ATD to the expecting mother may raise concern related to potential teratogenicity of the disease and/or the drug. To date, it remains uncertain whether untreated GravesÕ disease is associated with an increased frequency of congenital abnormalities. Drug-related, congenital anomalies include aplasia cutis congenita (absence of skin and accessory structures, usually over the scalp) and rare instances of severe embryopathy. The evidence linking aplasia cutis to maternal MMI is not conclusive, but it is also not sufficient to rule out a causal role. So far aplasia cutis has not been reported in mothers receiving PTU. In view of the potential dangers – for both mother and offspring – of not treating active GravesÕ disease during pregnancy, the concerns of rare congenital anomalies would not, in our opinion, justify withholding ATD administration. Third, the administration of ATD to treat pregnant women with GravesÕ disease may induce fetal hypothyroidism. As alluded to in an earlier section of this review, this should certainly be avoided in view of the potential deleterious consequences on the neuropsychointellectual development and can be avoided in practice by keeping maternal circulating thyroid hormone levels in the upper part of the normal range. Fourth, both the disease and its treatment can induce a fetal goiter. In these clinical circumstances, fetal goiter may result from the growth-stimulating effects of maternal TSHR-Ab and from the direct effects of ATD on the fetal thyroid gland. Fifth, unrecognized fetal hyperthyroidism may be followed by neonatal hyperthyroidism at birth. Neonatal hyperthyroidism is usually considered to be extremely uncommon, occurring in about 1% of pregnancies in patients with GravesÕ disease in North America. However, a recent reevaluation of this question suggests that the actual frequency of neonatal hyperthyroidism may be significantly higher (in the order of 2–10%). The risk is highest in the offspring of women with GravesÕ disease whose hyperthyroidism is not well controlled, as well as in those with the highest TSH receptor antibody titers. The relationship between the risk of neonatal hyperthyroidism and antibody levels is logical, in that higher titers of maternal antibody are more likely to be transmitted to the fetus. Usually, neonatal GravesÕ disease is diagnosed at or shortly following delivery, after the maternal antithyroid drugs have been cleared from the neonatal thyroid gland and serum [33–36].

3.4. Gestational transient thyrotoxicosis Gestational transient thyrotoxicosis (GTT) can be defined as non-autoimmune hyperthyroidism of variable severity that occurs in women with a normal pregnancy,

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typically in association with hyperemesis. GTT differs from GravesÕ disease in that it occurs in women without a past history of GravesÕ disease and in the absence of detectable TSH receptor antibodies. GTT is not always clinically apparent, since it is most often transient. Its etiology is directly related to the thyrotropic stimulation of the thyroid gland associated with hCG. Recent prospective studies from Europe have indicated that the prevalence of GTT may represent 2–3% of all pregnancies (that is 10-fold more prevalent than hyperthyroidism due to GravesÕ disease). In other regions of the world, however, the prevalences of GTT appear to be highly variable, perhaps as low as 0.3% in Japan, while as high as 11% in Hong Kong [6,37,38]. Owing to its transient nature, the clinical manifestations of the disorder are not always apparent or routinely detected. Symptoms compatible with hyperthyroidism including weight loss or the absence of weight increase, tachycardia and unexplained fatigue are found in only one half of the women with GTT. Hyperemesis is frequently associated with the most severely thyrotoxic cases in some women, the symptoms are sufficiently alarming to require hospitalization for treatment. In most cases of GTT, no specific treatment is required and the symptoms can be relieved by the administration of beta-adrenergic blocking agents for a short period (less than 2 months). In rare cases, the severity of the clinical presentation may require treatment with PTU (usually for only a few weeks). In the cases we have personally observed and followed until after parturition, GTT was always transient and serum free T4 normalized in parallel with the decrease in hCG concentrations, although serum TSH often remained partially or even totally suppressed for several weeks after free T4 had normalized. Also, GTT was not associated with a less favorable outcome during pregnancy. It should be noted that, by coincidence, GTT can occur in women with preexisting thyroid disorders such as glandular autonomy, autoimmune thyroiditis or cryptic GravesÕ disease. In the few cases we have witnessed over the past decade, such an association led to more severe clinical presentations of thyrotoxicosis, and may presumably help to explain the rare cases of exacerbation of thyrotoxicosis due to GravesÕ disease that are infrequently encountered during the first trimester of gestation. Finally, when women with GTT were followed during a subsequent pregnancy, the syndrome characteristically tended to reappear (unpublished observations). The precise pathogenic mechanisms underlying GTT are still not fully understood. It remains possible that abnormal molecular variants of hCG with a prolonged halflife are produced in these situations, explaining sustained high circulating hCG levels, or hCG variants with a more potent thyrotropic activity. It has also been hypothesized that a dysregulation of beta-hCG

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production may transiently take place in these women. Based on the example of GTT in twin pregnancies, a quantitative direct effect of elevated hCG may presumably be sufficient to explain GTT in most pregnant women, provided that hCG values remain above 75000– 100000 U/L for a sufficient period of time. We believe that GTT is directly related to both the amplitude and duration of peak hCG. Whatever the final explanation, the effects of hCG on stimulation of the thyroid gland can best be explained by the marked homology that exists between the hCG and TSH molecules, as well as between the LH/CG and TSH receptors. GTT can be considered an example of an endocrine ‘‘spill-over’’ syndrome, a concept based on the molecular mimicry between hormone ligands and their receptors [39–42]. An interesting, but unresolved, question is whether the thyroid gland is the ‘‘passive bystander’’ (or the victim) of abnormal thyrotropic activity of hCG in GTT, or whether the gland itself, through variable degrees of sensitivity of the TSH receptor, plays an active role in its responsiveness to the action of hCG. So far, only one fascinating example has been reported with a substantially increased sensitivity of the TSH receptor to the stimulatory effect of hCG, due to a single mutation in the extracellular domain of the TSH receptor (K183R). The mutant TSH receptor was more sensitive than the wild-type receptor to hCG, thus accounting for the recurrent hyperthyroidism during pregnancy in the presence of normal hCG levels. This finding raises the possibility that some women who develop GTT may have an abnormality at the level of the thyroid follicular cell. As of now, this situation remains exceptional since most cases with GTT do not seem to be familial and they almost invariably have hCG levels >100000 U/L [43,44]. GTT is often associated with nausea (morning sickness), increased vomiting and hyperemesis gravidarum, a severe condition requiring hospitalization and drastic treatment. Several studies have now established a correlation between the intensity of emesis and frequent abnormalities of thyroid function. A common observation among obstetricians is that women with a twin pregnancy often experience severe vomiting in the early stages of gestation. Since there is no indication of increased vomiting among pregnant women with GravesÕ disease, hyperemesis in pregnancy appears to be significantly associated with hCG-induced thyrotoxicosis, although not all cases of vomiting during early pregnancy are related to disturbances of thyroid function. The most likely explanation is that elevated and sustained hCG levels in the circulation promote estradiol production in these women. By a mechanism that is not yet fully understood, the combination of high hCG and estradiol levels, as well as increased free T4 concentrations transiently promotes emesis near the period of peak hCG.

4. Conclusions and perspectives Pregnancy has profound effects on the regulation of thyroid function and thyroid functional disorders that need to be recognized, carefully assessed, clearly understood and correctly managed [45,46]. Relative hypothyroxinemia and goitrogenesis may occur in healthy women who reside in geographical areas with only a restricted iodine intake, supporting the concept that pregnancy constitutes a stimulatory challenge for the thyroidal machinery. Overt thyroid dysfunction occurs in 1–2% of pregnant patients. Subclinical forms of thyroid dysfunction (both hyper- and hypothyroidism) are probably more prevalent and frequently unrecognized due to lack of implementation of specific screening programs designed to disclose thyroid function abnormalities in early gestational stages. Alterations of maternal thyroid function due to iodine deficiency, hypothyroidism, or hyperthyroidism have important implications for fetal and neonatal health and development [47–49]. In recent years, the potential risks for fetal development of hypothyroxinemia during early gestation has drawn particular attention. During the postpartum period, women with autoimmune thyroid disorders, in whom both hypo- and hyperthyroid phases are frequently encountered, should be carefully followed. The two main causes of thyrotoxicosis during pregnancy are GravesÕ disease (less common, but potentially life-threatening) and GTT (more common, but transient, usually mild and rarely severe). It is critical for the clinician to recognize that the natural history of GravesÕ disease is altered during pregnancy with a tendency for an exacerbation in the first trimester, an amelioration of the condition during the second and third trimesters and a typical re-exacerbation in the postpartum period. This natural history must be kept in mind when treating hyperthyroid patients, since all antithyroid drugs cross the placenta and can, to some extent, directly impair fetal thyroid function. Thus, the proper management of the pregnant patient with GravesÕ disease remains one of the most challenging aspects in clinical endocrinology [50]. Finally, there are several justifications for proposing to routinely screen pregnant women for thyroid dysfunction. Algorithms to this effect have been proposed in recent years, but until now they have not been implemented systematically, nor have they been subjected to prospective studies to evaluate their cost-effectiveness.

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