One of the challenges for endocrinologists and obstetric care providers remains the evaluation and management of hyperthyroidism in the pregnant patient, and in particular that of Graves' disease (GD). Hyperthyroidism during pregnancy is relatively uncommon, with a prevalence estimated to range between 0.1% and 1% (0.4% clinical & 0.6% subclinical) 46, 295-299. Causes of thyrotoxicosis include those found in the general population, as well as others that occur specifically during pregnancy. Etiologies such as single toxic adenoma, toxic multinodular goiter, subacute or silent thyroiditis, iodide-induced thyrotoxicosis, and thyrotoxicosis factitia are uncommon during pregnancy. Molar disease should always be considered as it can potentially lead to severe thyrotoxicosis, particularly in pregnant women with a pre-existing autonomous or nodular goiter. However, since uncomplicated hydatidiform mole is easily diagnosed in early gestation, it rarely leads to severe thyrotoxicosis 34, 35, 300, 301. Other extremely rare causes of hyperthyroidism (described recently as isolated cases) include hyperplacentosis and struma ovarii 302-304.
In women in the childbearing age, the most common cause of hyperthyroidism is GD, as this etiology accounts for 85% of clinical hyperthyroidism in pregnancy. Another cause of hyperthyroidism results directly from the stimulatory action of hCG on the thyroid and this etiology is associated with transient hyperthyroidism in the first half of gestation. Although the overall prevalence of hCG-induced hyperthyroidism is greater than that of GD, it is usually much less severe clinically and seldom requires treatment. This syndrome is referred to as gestational transient thyrotoxicosis (GTT) or gestational hyperthyroidism and differs fundamentally from GD in that it is not of autoimmune origin and, furthermore, the course, fetal risks, management and follow-up of both entities are entirely different 6, 25, 42, 44, 46, 50, 228, 297.
Even though the historical clues and physical findings are the same in pregnant and non pregnant patients, the diagnosis of thyrotoxicosis may be difficult to make clinically during pregnancy. Non specific symptoms such as fatigue, anxiety, tachycardia, heat intolerance, warm moist skin, tremor and systolic murmur may be mimicked by normal pregnancy. Alternatively, presence of goiter, ophthalmopathy and pretibial myxoedema obviously points to the suspicion of GD (see Table 14-13). A useful symptom of hyperthyroidism is that, instead of the customary weight gain, patients may report weight loss or, even more frequently perhaps, absence of weight gain despite an increased appetite (unless there is also excessive vomiting). Nausea (morning sickness) occurs frequently during normal pregnancy. However, the occurrence of hyperemesis gravidarum accompanied by weight loss must always raise the suspicion of hCG-induced hyperthyroidism.
|
Table 14-13 Clinical features suggesting the possibility of hyperthyroidism due to Graves' disease in a pregnant patient |
|
Historical Physical
examination |
Patients suspected of having hyperthyroidism require measurement of serum TSH, T4 and T3 levels, and anti-TSH receptor antibodies (TRAb). Virtually all patients with significant symptoms have a serum TSH <0.1 mU/L, as well as concurrent elevations in serum free T4 and T3 levels. However, interpretation of thyroid function tests must take into account the hCG-mediated decrease in serum TSH that occurs during pregnancy. Near the end of 1st trimester, at the time of peak hCG values, serum TSH levels may be transiently lowered to values below 0.4 mU/L in ~20% of euthyroid women 3, 5, 6, 20, 25, 36, 41, 73, 304, 305. Thus, the degree and duration of TSH suppression (mainly but not only) in 1st trimester must be considered in making the differential diagnosis. Concerning T4 and T3 levels, the pitfalls and necessary caution in the interpretation of serum free T4 and T3 have been discussed earlier (see the section on thyroid function parameters in normal pregnancy).
Patients with GD usually have positive thyroid antibodies (TG-Ab and TPO-Ab) and, therefore, antibody presence should alert the clinician to the possibility that autoimmune thyroid disease is the cause of symptoms evoking hyperthyroidism. Most patients with GD have detectable TRAb. Since TRAb production tends to undergo immunologic remission during the second half of pregnancy, detection of TRAb may depend upon gestational age at determination 306, 307. Presence of TRAb in 1st trimester is highly useful in helping make the differential diagnosis between GD and other causes of gestational hyperthyroidism.
Three clinical situations are important to consider: a) women with active GD diagnosed before pregnancy and who receive antithyroid drug (ATD) treatment; b) women who have had GD and are in remission or considered cured after prior treatment; and finally c) women in whom the diagnosis of GD has not been established before the onset of pregnancy, but who present positive TRAb.
An important clinical concept is that the risk of complications for mother and child is directly related to the duration and adequate control of maternal hyperthyroidism (see Table 14-14). The most common complication is gestational hypertension, with a risk of preeclampsia that is ~5-fold greater in women with uncontrolled hyperthyroidism. Other obstetrical complications include miscarriage, fetal malformation, placenta abruptio, preterm delivery and low birth weight 297, 305, 306, 308-310. With regard to the risk of miscarriage in women with elevated thyroid hormone levels, a recent study showed that women with a genetic resistance to thyroid hormone (hence, who were euthyroid but had elevated T4 levels) experienced a significantly increased miscarriage rate compared to normals 311. The hypothesis was that the elevated maternal thyroid hormone levels caused hyperthyroidism in the fetus not carrying the gene for thyroid hormone resistance. Congestive heart failure may occur in women left untreated or treated only for a short period of time in the presence of gestational hypertension or operative delivery 304, 312. In a recent study from Australia, the outcome of pregnancy was evaluated in women with unrecognized maternal GD 313. Results showed severe prematurity (mean gestational age of 30 weeks at delivery) associated with very low birth weight (<2 Kg) and neonatal hyperthyroidism requiring treatment with ATD. In contrast, for those patients in whom the diagnosis was made early and treatment started promptly, the outcome was excellent. In a report of a family presenting non-autoimmune hyperthyroidism due to an activating TSH receptor gene mutation, it was recently shown that premature delivery and low birth weight were consistent features associated with this unusual cause of thyrotoxicosis 314. Finally, in another study of 230 pregnant women with GD in Japan, no adverse impact on the outcome of pregnancy was found in patients with adequately treated Graves' disease 315.
Table 14-14: Adverse pregnancy outcome and lack of control of maternal hyperthyroidism |
||||
|
|
Poor control |
Less than adequate control |
Adequate control |
Ref N° |
|
Preeclampsia |
14-22% |
|
7% |
289 |
|
CHF * |
60% |
|
3% |
288 |
|
Thyroid storm |
21% |
|
2% |
285 |
|
Preterm delivery |
88% |
25% |
8% |
288 |
|
LBW ** |
23% |
|
10% |
290 |
Foot-note to Table 14-14: * CHF: congestive heart failure; ** LBW: low birth weight (< 2,500 g)
GD is an autoimmune disease and it is therefore important to consider that the production of TRAb may fluctuate during pregnancy and, in turn, influence the clinical course of the disease. Since GD tends to undergo immunologic remission during gestation, TRAb detection may depend upon gestational age at measurement 306. The classical course of Graves' disease during pregnancy frequently encompasses exacerbation of hyperthyroidism during 1st trimester and a gradual improvement in the 2nd half of gestation. Maternal production of TRAb may remain elevated even after a prior thyroidectomy or thyroid ablation using radioiodine, or the apparent cure of the disease by antithyroid drug (ATD) therapy given several years before pregnancy. In euthyroid pregnant women who have previously received ATD for GD but who are currently not receiving ATD treatment, the risk of fetal/neonatal thyrotoxicosis is negligible and, therefore, systematic measurement of TRAb is not mandatory. For a euthyroid pregnant woman (with or without thyroid hormone replacement therapy) who has previously been treated with radioiodine or undergone thyroid surgery for GD, the risk of fetal/neonatal thyrotoxicosis depends upon the level of TRAb produced by the mother. As a result, TRAb should be measured in early pregnancy to evaluate this risk. For pregnant women who take ATD for the treatment of active GD (assuming that ATD was started before or in early pregnancy), TRAb should be measured in the first and last trimesters. If TRAb titers have not substantially decreased during the 2nd trimester, the possibility of fetal thyrotoxicosis should be considered 46, 59, 228, 316. Radetti et al. showed that TRAb"s maternal transfer to the fetus in a hyperthyroid pregnant woman with active GD caused a marked increase in the fetal/maternal TRAb ratio 317. Thus, the fetal-placental unit gradually concentrates proportionally larger fractions of thyroid stimulating antibodies from maternal blood, particularly during the second half of gestation, hence underlining the importance to systematically search for fetal thyroid dysfunction in all clinical conditions where the mother may produce large amounts of TRAb. In a recent study by Peleg et al., it was confirmed that neonatal thyrotoxicosis occurred only in infants of mothers with high TRAb titers 318.
As indicated above, hyperthyroidism due to Graves' disease usually tends to improve gradually during gestation, although exacerbations can be observed in the first weeks. Several reasons may help explain this spontaneous improvement: the partial immunosuppressive state characteristic of pregnancy with progressive decrease in TRAb production; the marked rise in maternal serum TBG levels that tends to reduce serum free T4 & T3 fractions; obligatory iodine losses specific of pregnancy that may, paradoxically, constitute an advantage for women with GD; changes in cytokine production between normal and GD pregnant women may also help explain the transient remission of the disease; and finally, a suggestion was made that the balance between TRAb"s blocking and stimulating activities may be modified in favor of blocking antibodies 319-322. The reality of the latter finding, however, has been recently denied in another study from Japan 323. Among possible reasons for an exacerbation of thyrotoxicosis in women with GD during early pregnancy, one must keep in mind the potential coincidental stimulatory effect of high hCG levels, and this has recently been shown to occur in perhaps as many as 26% of such women 324.
Since TRAb may contain a mixture of auto-antibodies with different action types on the TSH receptor, there is room for confusion. All antibodies that can compete with TSH for binding to the TSH receptor are identified as thyrotropin-binding inhibitory immuno-globulins (TBII). These antibodies are measured using commercially available kits that record the percentage of inhibition of TSH binding to a membrane preparation of human or porcine TSH receptors. These assays do not measure the ability of antibodies to stimulate the TSH receptor, although binding and stimulation frequently go in parallel. Therefore, these assays are often used as surrogates for assays of TSH receptor stimulating antibodies. Antibodies that stimulate the receptor can be measured by their ability to stimulate cAMP production in a preparation of cell membranes containing the TSH receptor. Such assays are specific for the pathogenic antibody of GD, but they are not generally available in hospital or commercial laboratories. Some antibodies bind to the TSH receptor and inhibit the stimulating activity of TSH. Such antibodies may be clinically significant since they can cause hypothyroidism (including in the fetus), but they are usually measured only in a research setting. Their assay depends upon their ability to reduce cAMP production induced by TSH, in the setting of the stimulating assay described above 325.
Antithyroid drugs (ATD) are the main treatment for GD during pregnancy. The overall goal of therapy is to control maternal disease by maintaining the patient at a high euthyroid or borderline hyperthyroid level, while minimizing the risk of fetal hyperthyroidism or hypothyroidism by using the smallest possible dose of ATD. The treatment of GD with ATD in pregnancy has recently been reviewed in detail in several review articles by Marcos Abalovich et al., Jorge Mestman, David Cooper, Susan Mandel & David Cooper, Shane LeBeau & Susan Mandel, and Helen Marx et al. 1, 297, 299, 304, 326, 327.
Propylthiouracil (PTU), methimazole (MMI) and carbimazole (CMI) have been used during gestation. These medications inhibit thyroid hormone synthesis via inhibition of iodine organification and iodotyrosine coupling. Pregnancy itself does not appear to alter significantly the pharmacokinetics of ATD and both PTU and MMI (or CMI) appear equally effective 328. The ATD dosage should be maintained at a minimum and drugs discontinued, when feasible (often possible after six months of gestation). Combined administration of ATD and thyroxine to the mother should be avoided, since trans-placental passage of ATD is high while negligible for thyroid hormones and, hence, thyroxine will not protect the fetus from ATD-induced hypothyroidism.
All ATD cross the placenta and may therefore inhibit fetal thyroid function. PTU is more water soluble and more extensively bound to albumin at physiologic pH than MMI. Theoretically therefore, treatment with MMI may result in an increased trans-placental passage relative to PTU. These facts have led authors to recommend preferentially the use of PTU during pregnancy and lactation, based on the concept that the fetus and/or infant might be at higher risk of developing hypothyroidism when women receive MMI. From all the available information taken together, however, differential placental transfer of PTU and MMI appears unlikely and by itself does not support the preferential use of PTU versus MMI. Furthermore, MMI (or CMI) is commonly used in pregnancy in countries where PTU is not available (for instance, in Japan and several European countries), without particular problem. Therefore, the recommendation for the sole use of PTU does not appear to be justified. 76, 329-335.
General guidelines for the treatment of Graves' disease in pregnancy are summarized in Table 14-15. The principle of therapy is to administer the lowest dose of ATD needed for controlling clinical symptoms. Maintaining a mild degree of hyperthyroidism is acceptable as long as the patient tolerates this condition and pregnancy progresses satisfactorily. Patients should be followed closely, with careful monitoring of weight gain, heart rate, etc. A typical starting dose of ATD is 50-100 mg PTU twice daily (or the equivalent dosage for MMI/CMI). When both types of ATD are available, most clinicians prefer to use PTU than MMI. Monitoring ATD treatment monthly is necessary. After control of thyrotoxicosis, it is often possible to reduce the dose of ATD. The decision as to the maximal safe ATD dose during pregnancy is somewhat arbitrary, since the results vary with individual maternal-fetal pairs. Limits as widely variable as 150-450 mg/day have been suggested for PTU, but are of relatively little use in practice.
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Table 14-15. Treatment guidelines for Graves' disease during pregnancy |
|
|
1. |
Monitor pulse, weight gain, thyroid size, serum free T4 and T3, and TSH every 2-4 weeks, and titrate ATD as necessary. |
|
2. |
PTU is usually preferred to MMI, but both types of ATD can be used. |
|
3. |
Use the lowest dosage of ATD that maintains the patient in a euthyroid or mildly hyperthyroid state. The ATD dose can usually be adjusted downward after 1st trimester and often discontinued during last trimester. |
|
4. |
Do not attempt to normalize serum TSH. Serum TSH concentrations between 0.1 & 0.4 mU/L are generally appropriate, but lower levels are acceptable if the patient is clinically satisfactory. |
|
5. |
While as little as 100-200 mg PTU/day may affect fetal thyroid function, dosages as high as 400 mg PTU (~30 mg MMI) have been used. |
|
6. |
Communicate regularly with obstetric care providers, especially with respect to fetal pulse and growth in the 2nd half of gestation. |
|
7. |
Consider thyroidectomy if persistently high doses of ATD are required (PTU >600 mg/d or MMI >40 mg/d), or if the patient is not compliant or cannot tolerate the administration of ATD. |
|
8. |
Beta-adrenergic blocking agents and low doses of iodine may be used peri-operatively to control hyperthyroidism. |
|
9. |
ATD will often need to be reinstituted or increased after delivery. |
Propranolol may be used transiently to control symptoms of acute hyperthyroid disease and for pre-operative preparation, and there are no significant teratogenic effects of propranolol reported in humans or animals 336. If a patient requires long-term propranolol administration, careful monitoring of fetal growth is advised, because of a possible association with intrauterine growth restriction 337.
Chronic use of iodide during pregnancy has been associated with neonatal goiter and hypothyroidism, sometimes resulting in asphyxiation because of tracheal obstruction 329, 338. One study investigating the use of potassium iodide (6-40 mg/d), administered to selected hyperthyroid pregnant patients, showed improved maternal function with a normal neonatal outcome 339. Because the experience with iodides is limited, iodide should not be used as a first line therapy for GD during pregnancy, but can be used temporarily in preparation for thyroidectomy.
Radioactive iodine administration is contraindicated during pregnancy. In case of inadvertent radioiodine administration, the fetus is exposed to radiation from mother"s blood (approximately 0.5-1.0 Rad per milli-Ci administered). Since fetal thyroid uptake of radioiodine commences after the 12th week, exposure to maternal radioiodine prior to this time is not associated with fetal thyroid dysfunction 340. However, treatment with radioiodine after 12 weeks leads to significant radiation effects on the fetal thyroid. Multiple incidents of inadvertent exposure to radioiodine have been reported, causing fetal thyroid destruction, in utero hypothyroidism, and subsequent neural damage 341, 342.
Thyroidectomy for Graves' disease during pregnancy should be reserved as a second line of treatment in specific situations such as: a) persistent high ATD doses required to control maternal thyrotoxicosis; b) patients who present serious side effects to ATD (allergy, intolerance, etc.); c) patients who are non compliant; and finally d) rare cases with upper respiratory compressive symptoms due to goiter size. Thyrotoxic pregnant women should be prepared for surgery by using beta-blocking agents and a 10-14 days course of super-saturated potassium iodide solution (50-100 mg/d) in order to reduce vascularity of the thyroid gland. Surgery in pregnancy is deemed safest if it can be undertaken in the second trimester when organogenesis is complete, the fetus at minimal risks for teratogenic effects of medications, and the uterus relatively resistant to contraction-stimulating events 343.
The question of the safety of lactation during ATD therapy arises frequently 326. Historically, women have been advised against breastfeeding when receiving ATD because of the presumption that ATD was present in breast milk in concentrations sufficient to affect infant"s thyroid function. Both PTU and MMI are secreted in human milk, although PTU less so because of more extensive binding to albumin 344-347. In one study evaluating the effects of CMI (15 mg/d) or PTU (150 mg/d) on infants of nursing mothers, there was no evidence of neonatal hypothyroidism in the first weeks of life 348. In another study, serum MMI levels were measured in breastfed infants of thyrotoxic mothers receiving MMI (20-30 mg/d): two hours after MMI ingestion, serum MMI levels in the babies were extremely low, far below the therapeutic range 349. Thus, with both PTU and MMI, only limited quantities of the drugs are concentrated into milk. As long as the doses of MMI or PTU can be kept moderate (MMI: <20 mg/d; PTU: <250-300 mg/d), the risk for the infant is practically negligible and there is no evidence-based argument to advise mothers against nursing when they take ATD 304, 326, 350. The drug should be taken by the mother after a feeding and it is prudent to monitor the infant's thyroid function periodically during the time of ATD administration, although a recent study showed reassuringly that thyroid function was not affected in breastfed infants, even when ATD induced maternal hypothyroidism 351. There is also a possibility that allergic reactions associated with ATD (agranulocytosis or rash) may occur in the infant. While these side effects are rare, they should be kept in mind when evaluating a febrile infant or presence of rash. In summary, within the limitations outlined above, the use of ATD in lactating mothers does not pose a risk to the neonate and appears to be safe.
TRAb may have stimulatory or inhibiting effects on the thyroid gland 352. Thus, depending upon the balance between these opposite effects, TRAb production in pregnant women with GD may stimulate or inhibit the fetal thyroid gland. Inhibitory TRAb production has been shown to cause hypothyroidism transiently in neonates born to mothers with GD 156, 353.
When maternal TRAb production with stimulating activity is elevated and antibody titers do not substantially decrease in the second part of gestation, fetal (and neonatal) hyperthyroidism constitutes a real risk 316-318, 354. One to 5% of neonates of mothers with GD have hyperthyroidism (neonatal GD) due to the trans-placental passage of stimulating maternal TRAb. The overall incidence is low because of the balance between stimulatory and inhibitory antibodies, and also maternal treatment with ATD 316. The incidence of neonatal GD is not directly related to maternal thyroid function. Risk factors for neonatal thyroid dysfunction include history of a previously affected baby, prior radioiodine ablative treatment, and elevated TRAb titers at delivery 315, 316, 318, 355. In the study by Mitsuda et al. for instance, the incidence of neonatal thyroid dysfunction was 67% when maternal TRAb was >130% and as high as 83% when TRAb was >150%, compared with only 11% when TRAb was <130% of normal (normal TRAb in this study was <115%) 315.
The risk of fetal hyperthyroidism can be assessed by fetal ultrasonographic data, showing the presence of fetal goiter, tachycardia, growth retardation, increased fetal motility, and accelerated bone maturation 305, 356. When fetal hyperthyroidism is suspected in utero, it is reasonable to initiate ATD treatment with PTU (200-400 mg/d) or MMI (20 mg/day) combined with thyroxine administration, when required, to maintain maternal euthyroidism. ATD treatment may thus be given based on a presumptive diagnosis, but the definitive diagnosis of fetal hyperthyroidism may require umbilical cord blood sampling for fetal thyroid hormone determination. This procedure carries, however, a significant risk for the fetus (complications and/or fetal loss in 1% of cases) 357-361.
Administration of ATD to treat maternal GD may induce fetal hypothyroidism that should be avoided in view of its potential deleterious consequences for the neuro-psychointellectual development. In clinical practice, the best way to avoid fetal hypothyroidism is to keep maternal circulating thyroid hormone levels in the upper quartile of the normality range 335, 362, 363. As alluded to above already, radioactive iodine has unintentionally been administered (in exceptional cases) to GD women who were unaware that they were pregnant and who decided, nevertheless, to maintain the pregnancy. In one such recently published case report, the authors showed the advantage – despite the obvious risks associated therewith – of performing cordocentesis to predict the fetal outcome 364.
Subclinical hyperthyroidism (defined as a serum TSH below normal limits with free T4 and total T4 levels in the normal pregnancy range, and unaccompanied by specific clinical evidence of hyperthyroidism) can be observed in maternal GD, although it is more often found in association with gestational transient thyrotoxicosis. Treatment of maternal subclinical hyperthyroidism has not been found to improve pregnancy outcome and may risk unnecessary exposure of the fetus to antithyroid drugs 357, 363, 365-367.
The treatment of maternal hyperthyroidism may be associated with the presence of fetal goiter, thus raising clinical concern with regard to its etiology and management. Fetal goiter may result directly from the placental transfer of thyroid growth-stimulating effects of maternal TRAb, as well as from ATD"s inhibitory effect on the fetal gland inducing fetal hypothyroidism 368-373. This complex – but highly important – topic was recently revisited. Gallagher et al. showed that the spectrum of neonatal thyroid dysfunction in pregnant women with GD receiving ATD ranged from frank hypothyroidism (secondary to the exposure to PTU and maternal blocking TRAb) to neonatal Graves' thyrotoxicosis (secondary to exposure to maternal stimulating TRAb) and that the prenatal diagnosis remained often extremely complex 374. The group of Michel Polak in Paris reported their experience on a large group of mothers with past or present GD, who had been investigated using clinical evaluation, TRAb measurements, as well as ultrasound evaluation of the fetal thyroid and bone age 373, 375. Details of the main results are shown on Figure 14-16 (upper panel). In 31 pregnancies with no detectable TRAb and mothers without ATD treatment, all infants were normal at birth. In the remaining 41 pregnancies, 30 women had positive TRAb and/or a treatment with ATD: fetal thyroid ultrasound was normal (32 wks gestation) and there was almost no evidence of fetal thyroid dysfunction. Finally, 11 fetuses were found to have a goiter, of which 7 were hypothyroid and 4 hyperthyroid. Figure 14-16 (lower panel) outlines the main risk factors for fetal hyper- and hypothyroidism when a fetal goiter is found in women with ATD treated GD. Based on their observations, the authors recommended TRAb measurement in women with current or past GD at the beginning of pregnancy, and close observation of those pregnancies with elevated TRAb or ATD treatment by performing monthly fetal ultrasonography after 20 weeks of gestation.
|
Figure 16: Upper panel: data on 72 mothers with Graves' disease (adapted from the study of Luton et al., Ref 373). Lower panel: main risk factors for fetal hyperthyroidism and hypothyroidism associated with fetal goiter in mothers with Graves' disease (adapted from Chan & Mandel, Ref 376). |
Both thyrotoxicosis by itself and the administration of ATD to the expecting mother may raise concern with regard to potential teratogenicity associated with the disease and the medications. To date, it remains uncertain whether untreated GD is associated with a higher frequency of congenital abnormalities 315, 326, 376. Concerning the antithyroid drugs, there have been reports of two distinct teratogenic patterns associated with the administration of MMI, namely aplasia cutis congenita and choanal/esophageal atresia, although data supporting these associations remain somewhat controversial 377-380. Aplasia cutis is the absence of skin and accessory structures over the scalp and has, so far, not been reported (or only exceptionally) in mothers receiving PTU. The so-called "methimazole embryopathy" includes congenital abnormalities such as choanal and/or esophageal atresia, minor dysmorphic features and developmental delay 305. After reviewing the evidence linking ATD treatment with such fetal abnormalities, one comes to the conclusion that the prevalence of these malformations remains extremely rare: 2/241 MMI-exposed infants, for instance, in the series reported by Di Gianantonio 381. A recent case report from Japan illustrates the complexities in our understanding of fetal abnormalities found in association with MMI administration during pregnancy. The authors reported the case of a monozygotic twin with aplasia cutis after in utero exposure to MMI, namely that of a girl born at 36 weeks gestation. Her mother had received MMI: 15-30 mg daily, from the 11th to 17th week of pregnancy. However and to everybody"s surprise, the second child of these monozygotic twins did not have aplasia cutis 382.
In view of the potential danger – both for mother and offspring – of not treating active GD during pregnancy, the concern posed by these rare congenital abnormalities would not, in our opinion, justify withholding ATD administration. However, despite the fact that the link between severe congenital defects and MMI exposure during pregnancy has not been formally established, it appears prudent to avoid the use of MMI during embryogenesis and to prefer the use of PTU, when available.
Undetected fetal thyrotoxicosis may be followed by thyrotoxicosis at birth. Neonatal thyrotoxicosis is considered to be uncommon, occurring in ~1% of pregnancies in patients with Graves' disease in North America 5, 156. In a recent reevaluation of this topic, it was suggested that the actual prevalence of neonatal thyrotoxicosis may be significantly higher, in the order perhaps of 2-10% 304, 316. Risks appear highest in the offspring of women with not-well-controlled GD, as well as in women with the highest TRAb titers. Mothers with a prior history of bearing infants with neonatal GD are also at high risk of repeated episodes 156, 159. Neonatal GD is usually diagnosed at or shortly following birth, after maternal ATD has been cleared from neonatal serum and thyroid gland. Signs of neonatal thyrotoxicosis include congestive heart failure, goiter, proptosis, jaundice, hyperirritability, failure to thrive, and tachycardia. Once considered, the diagnosis should be readily confirmed. Cord serum free T4 and TSH determinations should be performed in all deliveries of mothers with a history of GD. Treatment should be initiated out in conjunction with the neonatalogist, and may include iodide, ATD, glucocorticoids, digoxin, and beta-adrenergic blocking agents, depending on the cardiovascular status. Neonatal hyperthyroidism may have a delayed onset in some infants, particularly those in whom both anti-TSH receptor blocking and stimulating antibodies coexist. Thus, the pediatrician should be alerted to measure serum free T4 if symptoms suggesting thyrotoxicosis appear during the first 6-8 weeks of life, even if cord serum results were normal, and especially when cord serum TSH was suppressed 326, 356, 360, 362, 383-385.
There have been several reports of infants who presented central congenital hypothyroidism, being born to mothers with uncontrolled hyperthyroidism due to GD 304, 386, 387. The explanation is based on the notion that high maternal serum T4 levels, during a prolonged period of time, crossed the placental barrier and suppressed fetal TSH by pituitary feedback. In most cases, the diagnosis was made at birth or shortly thereafter, on the basis of a low neonatal serum total T4 contrasting with an inappropriately low serum TSH. In the majority of these infants, there was a return to euthyroidism within a few weeks or months. However, a recent publication has suggested that in children born to mothers with inadequately treated GD during pregnancy, there may also be a risk of thyroid "disintegration" (i.e. abnormal ultrasound patterns found during childhood), possibly as the result of prolonged central hypothyroidism 388.
Two major forms of hyperthyroidism can be observed in the early postpartum period. They are due to GD or hyperthyroidism related to postpartum thyroid dysfunction (PPTD). Both entities have in common that serum TSH is suppressed and free T3 & T4 levels elevated; both diseases can present shortly after delivery and are associated with enlargement of the thyroid gland and presence of TPO-Ab. Presence of exophthalmos, a bruit, and positive TRAb are characteristic of GD. However, infrequently, women with PPTD may also be TRAb-positive. From an epidemiological standpoint, the most likely etiology of postpartum hyperthyroidism is PPTD, as its prevalence is much greater than that of GD (4.1 vs. 0.2%) 152, 305, 389-391. For the differential diagnosis between these entities, a thyroid scan can be required. Women with PPTD have a marked diminution of tracer uptake by the thyroid, contrasting with the increased tracer uptake that is typical of GD. In women with very mild hyperthyroidism during postpartum, it is reasonable to repeat thyroid function tests 4 to 6 weeks later, prior to scanning. In this condition, the gradual resolution of hyperthyroidism is consistent with a transient hyperthyroid phase associated with PPTD, and would therefore obviate the need for thyroid scanning 392. When patients present clinically overt hyperthyroidism related to PPTD, the diagnosis can perhaps be predicted based on the titers of thyroid antibodies during early pregnancy and an abnormal thyroid echogenic pattern at ultrasound examination during early postpartum 393, 394. Concerning GD, it is important to note that the disease often recurs during postpartum and also that a clinically significant number of women develop GD de novo after childbirth 395-397.
The two most common causes of hyperthyroidism during pregnancy are Graves' disease (GD) and gestational transient thyrotoxicosis (GTT). If a subnormal serum TSH is detected during gestation, hyperthyroidism must be first distinguished from normal gravid physiological changes and hyperemesis gravidarum. Differentiation of GD from non autoimmune GTT is supported by evidence of typical goiter and autoimmunity, specifically presence of anti-TSH receptor antibodies (TRAb).
For the treatment of active GD in pregnancy, antithyroid drug (ATD) therapy should be initiated (or adjusted) with the aim to control maternal hyperthyroidism. Maternal free T4 levels should be maintained in the upper non pregnant reference range.
Both PTU and MMI can be used during pregnancy, but it is recommended to use PTU as a first line drug, if available.
Thyrotoxicosis by itself and ATD administration may raise concern related to potential teratogenicity of the disease or/and the drug (aplasia cutis; choanal/esophageal atresia); such congenital defects are rare and do not justify withholding ATD administration.
An important concept is that maternal and fetal outcome is directly related to adequate control of thyrotoxicosis. Obstetrical repercussions of poorly controlled thyro-toxicosis include risks of miscarriage, gestational hypertension, fetal malformation, premature delivery and low birth weight.
Maternal GD can affect the fetus in several ways. TRAb freely cross the placenta to stimulate the fetal thyroid. These antibodies should be measured before pregnancy or by the end of the second trimester in mothers with current GD, a history of GD and prior curative treatment (by radioiodine or thyroidectomy), or a previous neonate with GD at birth. Women with negative TRAb and who do not require ATD have a very low risk of fetal or neonatal thyroid dysfunction. In women with positive TRAb, fetal & neonatal thyrotoxicosis constitutes a real risk when maternal TRAb titers have not substantially decreased during the second half of gestation. In women with elevated TRAb or receiving ATD, fetal ultrasound should be performed to search for evidence of fetal thyroid dysfunction.
Umbilical blood sampling should be considered only if the diagnosis of fetal thyroid disease is not reasonably certain from the clinical data and if the information gained would change the treatment.
All newborns of mothers with GD should be evaluated for thyroid dysfunction and treated when necessary.
In breast-feeding mothers who take ATD, there is no evidence-based argument to advise them against nursing, as long as the doses of ATD can be kept moderate.
The thyroid stimulating activity of human chorionic gonadotropin (hCG), its stimulatory effects on maternal thyroid function and its causal relation with hyperemesis gravidarum (HG) have already been discussed in the first section of this chapter (see "Effects of hCG on thyroid function" and "Hyperemesis Gravidarum").
Non autoimmune gestational hyperthyroidism or gestational transient thyrotoxicosis “GTT” is characterized by elevated serum free T4 and T3 levels, suppressed TSH, variable clinical evidence of hyperthyroidism, usually minimal thyroid enlargement, and absence of thyroid auto-antibodies. The syndrome occurs transiently near the end of the 1st trimester of gestation, usually in hitherto healthy women who have otherwise a normal pregnancy, and it is frequently associated with excessive vomiting 6, 14, 39, 41, 42, 350, 398. GTT differs fundamentally from GD in that it occurs in women without past history of GD and absence of detectable anti-TSH receptor antibodies (TRAb). GTT is not always clinically apparent, due to its transient nature. Its etiology is related to the thyrotropic stimulation of the maternal thyroid gland associated with elevated hCG levels (see Figure 14-17).
The prevalence of GTT is highly variable in populations of normal pregnancies. Prospective studies carried out in Europe have indicated that the prevalence may reach 2-3% of unselected pregnancies (that is 10-fold more prevalent than GD) 208. In other regions of the world, the prevalence of GTT appears to be as low as 0.3% (Japan) or as high as 11% (Hong Kong) 399, 400.
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Figure 17: Human CG levels measured at different time points during gestation in women with a diagnosis of GTT. The curve flanked by the dashed lines in the lower part of the graph represents the mean hCG levels (with 95% confidence intervals) determined in a cohort of normal pregnancies, showing the classical hCG peak near the end of the first trimester. The individual points show serum hCG levels in fifteen women with GTT, at the time of their recall, i.e. 3-6 weeks after initial screening for thyroid function. Initial diagnosis was based on suppressed serum TSH with elevated free T4 concentrations. All women clearly had abnormally elevated hCG values, even when the measurements took place several weeks after peak hCG. In a few cases, hCG was measured again during follow-up in the 2nd trimester and the results showed sustained abnormally elevated serum hCG levels. (from Glinoer, Ref 32) |
Owing to the transient nature of the syndrome, clinical manifestations of hyperthyroidism are not always apparent or routinely detected. When women followed in our institution were specifically questioned about possible symptoms compatible with thyrotoxicosis, we found weight loss (or absence of weight increase), tachycardia and unexplained fatigue in one half of the women with GTT. Hyperemesis gravidarum was frequently associated with the most severe cases, and in a few women symptoms were sufficiently alarming to justify hospitalization for treatment. In cases followed until parturition, GTT was always transient; elevated serum free T4 values reverted gradually to normal in parallel with the decrease in hCG concentrations. Serum TSH often remained partially (or totally) suppressed for several weeks after free T4 reverted to normal, i.e. until after mid-gestation 401, 402. GTT was not associated with a less favorable outcome of pregnancy. It should also be noted that GTT may occur, by coincidence, in women with preexisting thyroid disorders, such as glandular autonomy, autoimmune thyroiditis or GD, and even in women with genetic resistance to thyroid hormone 403. The association of GTT with an underlying thyroid abnormality often leads to more severe presentations of thyrotoxicosis. The stimulatory effect of hCG may also help explain the exacerbation of thyrotoxicosis due to GD, that is sometimes encountered during the 1st trimester 324. Finally, when women with GTT are followed in subsequent pregnancies, the syndrome has a characteristic tendency to relapse.
Twin pregnancy & gestational transient thyrotoxicosis (GTT)
Normal women develop GTT essentially when they have abnormally elevated peak hCG levels and when these very high hCG values are sustained during an unusually prolonged period 404. Twin pregnancy is a naturally occurring clinical condition associated with sustained and high hCG concentrations (see Figure 14-18). Peak hCG values were shown to be significantly higher (almost double) and of a much longer duration in women with a twin pregnancy. While peak hCG values lasted only for a few days in singleton pregnancy, peak hCG levels (>100,000 UI/L) lasted for up to six weeks in twin pregnancies. Twin pregnancy was associated with a more profound and 3-fold more frequent suppression of serum TSH values. Also, while serum free T4 levels remained unaltered in singleton pregnancy, they often rose transiently above normal in twin pregnancy. Symptoms related to thyrotoxicosis were usually mild or absent, except for more intense vomiting which was more frequently noted (obstetricians often observe increased nausea and vomiting in women with a twin pregnancy).
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Figure 18: Profiles of changes in hetero-dimeric intact hCG, serum free T4 and serum TSH, comparing women with singleton (pale blue) and thirteen women with a twin pregnancy (pink color). Each point corresponds to the mean (± 1 sd) of individual serum samples measured at each gestational age (from Grün et al., Ref 404). |
No trial has been carried out to delineate precisely which patients with GTT require a specific treatment. In most cases, no specific treatment is required and symptoms can be relieved by administration of beta-adrenergic blocking agents for a short period, while waiting for the spontaneous recovery of elevated thyroid hormones to occur. In patients with a severe clinical presentation (clear symptomatic hyperthyroidism), some – but not all – authors suggest starting treatment with PTU, usually for a few weeks only. Therapy is often discontinued by mid-gestation. As already indicated in the section on treatment for GD, the treatment of subclinical hyperthyroidism has not been found to improve pregnancy outcome and may risk unnecessary exposure of the fetus to ATD 357, 363, 365-367.
The precise pathogenic mechanisms underlying GTT are still not fully understood but the etiology of the syndrome is felt to be hCG itself or derivatives of hCG 14. Based on the example of GTT associated with twin pregnancy, a direct quantitative effect of elevated hCG concentrations to stimulate the thyroid gland is probably sufficient to explain hyperthyroidism in most pregnant women, provided that hCG remains above 75,000-100,000 UI/L for a sufficient period of time. Thus, GTT is directly related to both the amplitude and duration of peak hCG values 404. Human CG acts as a weak TSH agonist to increase cAMP production, iodide transport and cell growth in thyrocytes 42, 49, 50. It remains possible that abnormal h CG molecular variants, with a prolonged half life, are produced in these situations explaining sustained prolonged high circulating hCG levels 30. It has also been hypothesized that a dysregulation of beta-hCG production may transiently take place in these women 24. Finally, hCG molecular variants with a more potent thyrotropic activity have been detected, although these variants appear to be more specifically found in women with hydatidiform mole or choriocarcinoma 405-407. Whatever the final explanation, hCG effects to stimulate the thyroid can be best explained by the marked homology between hCG and TSH molecules, as well as between LH/CG and TSH receptors 408, 409. Gestational non autoimmune hyperthyroidism can be considered an example of an endocrine "spill-over" syndrome, a concept based on molecular mimicry between hormone ligands and their receptors 14, 50, 300, 405.
An interesting – although unresolved – question is whether the thyrocyte is a passive bystander of abnormal thyrotropic activity of hCG in GTT, or whether the thyrocyte itself, through variable degrees of sensitivity of the TSH receptor, may play an active role in its responsiveness to hCG"s stimulatory effect. A woman with recurrent gestational hyperthyroidism was reported by Rodien et al. in 1998 410. After two miscarriages, she presented hyperemesis with overt hyperthyroidism early in pregnancy, requiring treatment with PTU. During her next pregnancy, she experienced a relapse of the same situation. The patient"s mother had also been diagnosed with hyperthyroidism during her 2nd and 3rd gestations, mistakingly considered to be GD. Study of the TSH receptor of this patient disclosed a single mutation in the extracellular domain of the TSH receptor (K183R), rendering the mutant receptor highly sensitive to hCG, and accounting for recurrent thyrotoxicosis during pregnancies in the presence of normal hCG levels. Thus so far, only one fascinating example has been reported of a substantially increased sensitivity of the TSH receptor to the stimulatory effect of hCG in humans. This unique finding raises the possibility that some women who develop GTT may have an abnormality at the level of the thyroid follicular cell (see Figure 14-19). In further studies of structure-phenotype relationship at the level of the TSH receptor, the group of Gilbert Vassart carried out site-directed mutagenesis, substituting lysine 183 in the ecto-domain of the TSH receptor by a variety of amino acids expressing different physicochemical properties 16, 411. Somewhat unexpectedly, all mutant TSH receptors displayed a widening of their specificity toward hCG stimulation. Modeling of the mutated receptors indicated that the increased gain of sensitivity might result from the release of a nearby glutamate residue (in position E157) from a salt bridge formed with K183. As of now, this situation remains exceptional since most patients with gestational non autoimmune transient hyperthyroidism do not seem to be familial and almost invariably have hCG levels >100.000 UI/L 412.
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Figure 19: TSH receptor mutation, with a Lysine to Arginine mutation in position 183 of the ecto-doamin. The graph on the left shows that the mutation confers high sensitivity to hCG (red curve), compared with wild type TSH receptor (blue curve). The family tree (upper right) shows the pedigree of the patient. (from Rodien & Vassart, Refs 410-412). |
As alluded to in the first sections of this Chapter, GTT is often associated with nausea (morning sickness), increased vomiting and hyperemesis gravidarum, a severe condition requiring hospitalization and drastic treatment. Several studies have established a correlation between the severity of vomiting and abnormal thyroid function. Thirty to sixty percent of patients with hyperemesis gravidarum have elevations of free thyroid hormone concentrations, along with a suppressed TSH, and in the absence of any evidence of Graves' disease 38, 42, 413. A common observation among obstetricians is also that women with a twin pregnancy often experience more severe vomiting during early gestation. Increased vomiting is not customary associated with hyperthyroidism due to GD in pregnancy. Thus, hyperemesis appears to be associated mainly with hCG-induced thyrotoxicosis, although evidently all women who vomit during early pregnancy do not have disturbances of thyroid function. One likely explanation is that elevated and sustained hCG levels in the circulation promote estradiol production in these women; the combination of elevated hCG, estradiol and free T4 concentrations then transiently promotes emesis near the period of peak hCG, by some yet not fully understood mechanism 14, 42, 50, 400, 405. A recent matched-paired study in fifty-eight pregnant Chinese women showed that women with hyperemesis gravidarum were younger and had higher serum free T3 and T4 levels, as well as higher -hCG concentrations 414. In this study, logistic regression analysis of the data showed that the principal determinant for having hyperemesis was the high free T4, and not the high hCG levels. Thus, these results reinforce the concept that hCG is not independently involved in women with hyperemesis gravidarum, but rather indirectly by stimulating the thyroid to induce gestational hyperthyroidism.
Recently, the first case report was published of a woman with a partial molar pregnancy who presented hyperthyroidism leading to a thyrotoxic storm 415. This case presented two interesting clinical features. The first feature was that the mole was "partial", hence allowing a viable pregnancy to proceed up to 13-14 weeks, but also severe thyrotoxicosis to develop. The second feature was that there was an unusually long time lag between the different clinical events. The diagnosis of hyperemesis gravidarum had been made four weeks before admission and hyperthyroidism was already present at that time. Thereafter, the clinical situation continued to deteriorate rapidly, eventually leading to the classical picture of a thyrotoxic storm, rapidly cured by the evacuation of the molar pregnancy.
Gestational hyperthyroidism or transient thyrotoxicosis (GTT) is defined as a transient increase in thyroid hormone production, of non-autoimmune origin, leading to variable degrees of hyperthyroidism and frequently associated with hyperemesis. The prevalence of the syndrome is 2-3 % of all pregnancies.
Thyroid function tests should be measured in all patients with hyperemesis gravidarum.
A quantitative direct effect of elevated hCG to stimulate the thyroid gland explains most cases with GTT, when hCG remains above 100,000 UI/L for a prolonged period of time. GTT is directly related to the amplitude and duration of peak hCG values and can therefore be considered as an example of endocrine spill-over syndromes, a concept based on molecular mimicry between hormone ligands (TSH & hCG) and their respective receptors.
Owing to the transient nature of GTT, clinical hyperthyroidism is not always apparent, and symptoms suggesting thyrotoxicosis are found in ~50% of women with GTT.
In most cases, no specific treatment is required; symptoms can be relieved by beta-adrenergic blocking agents. In rare cases, severe clinical presentation may require treatment with PTU as long as clinically necessary, usually less than two months.
Concerning emesis, the most likely explanation is that elevated hCG levels promote estradiol production and that the combination of high hCG, estradiol and free T4 concentrations promotes emesis near the period of peak hCG.
