Abstract
Pregnancy has marked effects on thyroid physiology and autoimmune thyroid disease tends to ameliorate through gestation due to the general immunosuppression seen in pregnancy. There is a need for trimester-specific thyroid hormone reference ranges. Hyperthyroidism in pregnancy – usually due to Graves' disease – is not common but, if the patient is compliant, a good outcome can be expected for both mother and child if treatment with anti-thyroid drugs (propylthiouracil is preferred) is instituted. Thyroid-stimulating hormone receptor antibody should be measured at 36 weeks in such patients in order to predict the possibility of neonatal hyperthyroidism. Transient gestational hyperthyroidism is often associated with hyperemesis gravidarum and thyroid function should be checked in patients severely affected by this condition. Radioiodine therapy is contraindicated in pregnancy but thyroid surgery may be performed safely in the second trimester. Autoimmune thyroiditis and Graves’ hyperthyroidism occur quite commonly in postpartum women.
Keywords
The prevalence of Graves' disease is approximately 3/1000 with an incidence of around 0.5/1000/year. The prevalence and incidence in women during child bearing years is not known but hyperthyroidism is said to occur in 2/1000 pregnancies and Graves' disease would be expected to account for at least 80% of these cases. While these figures are low, untreated or poorly controlled hyperthyroidism can have a deleterious effect on the mother as well as the fetus. The thyroid hormone changes and immunologic effects of normal pregnancy will be reviewed as a background to the management of hyperthyroidism during pregnancy. The subject has been reviewed previously [1–3].
Pregnancy & the thyroid
Hormonal changes
It has been known for some time that pregnancy has an appreciable effect on thyroid economy [4]. There are significant changes in iodine metabolism characterized by increased excretion of iodine in the urine; this iodine loss may account for the increase in thyroid volume even in areas of moderate dietary iodine intake and the substantially greater increase in volume in iodine-deficient areas [5]. Thyroid hormone transport proteins, particularly thyroxine binding globulin (TBG), increase in the first trimester due to enhanced hepatic synthesis and a reduced degradation rate caused by oligosaccharide modification. Serum concentrations of thyroid hormones have been reported to be decreased, increased or unchanged during gestation.
The placenta secretes human chorionic gonadotropin (hCG), a glycoprotein hormone sharing a common α subunit with thyroid-stimulating hormone (TSH) but having a unique β subunit, which confers specificity. Evidence derived both from in vitro studies on thyroid tissue, and on eukaryotic cells stably expressing the human TSH receptor (TSHR), suggests that hCG, or a molecular variant, is able to act as a TSH agonist. The impact of the physiologic changes on thyroid function is shown in Table 1 [6].
Physiologic changes in pregnancy that influence thyroid function tests.
Adapted from Brent [6]. hCG: Human chorionic gonadotropin; TSH: Thyroid-stimulating hormone.
Immune changes
Pregnancy has a profound effect on the immune system, in order to maintain the fetal–maternal allograft, which is not rejected despite displaying paternal histocompatability antigens [7]. While there is no overall immunosupression during pregnancy, dramatic clinical improvement usually occurs in patients with immunologic disorders such as rheumatoid arthritis (RA) when they become pregnant. T-cell subset studies in pregnancy are discrepant, as peripheral blood CD4+ and CD8+ cell levels have been variously reported to decline, remain unchanged and increase during pregnancy [7]. Although the distinction between T-helper cell (Th)1 and Th2 responses in humans remains less clear than in the mouse, the general agreement is that in pregnancy there is a bias towards a Th2 response [8]. This seems to be achieved by the fetal–placental unit producing Th2 cytokines, which inhibit Th1. Th1 cytokines are potentially harmful to the fetus as interferon is a known abortifacient.
The high concentrations of estrogen produced in normal pregnancy almost certainly contribute to the fall in autoantibody levels observed in pregnant patients with autoimmune thyroid disease (AITD) [9]. Despite the fall in autoantibodies, there are no significant changes reported in the number of B-cells in the circulation in normal human pregnancy. While progesterone may favor Th2 cells, evidence has indicated that estrogen delivers a negative signal to B-cell function during pregnancy and this showed a slow reversal in the postpartum period. In keeping with these observations, autoantibody titers and inflammation fall throughout pregnancy as observed in all autoimmune diseases investigated [10]. However, after most pregnancies, there is a marked increase in many different types of autoantibody secretion and an exacerbation of diseases in the months after delivery, not just AITD but, for example, also in patients with multiple sclerosis or RA. An outline of the immunologic and hormonal changes during gestation in relation to autoimmune thyroid disease is shown in Table 2 [2].
Immunologic and hormonal features of pregnancy.
HLA: Human leukocyte antigen; Th: T-helper cell.
Adapted from Lazarus [2].
Causes of hyperthyroidism in pregnancy
Etiology
While the most common cause of hyperthyroidism in pregnancy (which affects up to 0.2% of pregnant women) is Graves' disease (85–90%), other causes such as hyperemesis gravidarum, toxic multinodular goiter, toxic adenoma, and subacute thyroiditis may occur. It should be noted that most women with nausea and vomiting in pregnancy do not have hyperthyroidism although the levels of TSH may be below normal at this time of gestation. Rarer causes include struma ovarii, hydatidiform mole and one reported case of a TSHR mutation activated only during pregnancy resulting in familial recurrent gestational thyrotoxicosis due to hypersensitivity to hCG of the mutant TSHR [11].
This latter unique case has drawn attention to the close association of gestational transient thyrotoxicosis and hyperemesis gravidarum. Gestational transient hyperthyroidism is due to spillover of hCG onto the TSHR [12].
Clinical aspects & diagnosis
The clinical presentation of hyperthyroidism may not be obvious, as the symptoms of tachycardia, sweating, dyspnea and nervousness may be seen in normal pregnancy. Cardiac systolic flow murmurs occur in normal pregnancy as well as hyperthyroidism.
The diagnosis of hyperthyroidism in pregnancy is made by routine measurement of circulating thyroid hormones and TSH by a sensitive assay. Free T4 and T3 as opposed to total T4 and T3 assays are preferred by some as there is no interference resulting from the estrogen-stimulated increase in TBG concentrations. Recent national and internationally agreed guidelines [13] suggest that laboratories should be encouraged to develop normal ranges for levels of total, but more particularly free, T4 and T3, as well as TSH [14–16], all of which may change during the course of gestation. As TSH may be suppressed in early pregnancy due to the secretion of hCG, serum TSH alone is usually not adequate to assess thyroid status in early gestation but has a high specificity in later pregnancy. Radioiodine uptake studies are contraindicated during pregnancy but thyroid ultrasound will indicate the diffuse nature of the thyroid gland. The diagnosis of Graves' disease is made clinically by noting the presence of a positive family history of autoimmune thyroid disease and/or by the finding of a diffuse goiter together with extrathyroidal signs of ophthalmopathy or dermopathy (not seen in gestational hyperthyroidism) and biologically, if necessary, by measurement of TSHRAb.
Due to the immune changes already referred to, the titer of TSHR antibodies (TSHRAb – Table 3) will decline during gestation along with that of anti-thyroid peroxidase antibody (anti-TPO Ab). Thus, at 36 weeks TSHRAb may be negative; if still positive at this time, the risk of neonatal hyperthyroidism due to the transplacental passage of maternal antibody is high. Measurement of TSHRAb is particularly important in a woman previously treated for Graves' hyperthyroidism by destructive therapy and known to be euthyroid during gestation. In this situation a false sense of security in relation to the development of neonatal hyperthyroidism may be engendered if TSHRAb are not measured at 36 weeks. Cases of neonatal hyperthyroidism have been recorded whose mothers have been treated by surgery for hyperthyroidism and who have been receiving thyroxine therapy for postsurgical hypothyroidism while pregnant.
Guidelines for measurements of TSH-receptor antibodies in a pregnant women with Graves' disease.
TSH receptor antibodies may be measured by a ‘binding’ assay in which the result is expressed as the percentage inhibition of TSH to thyroid membranes by the test serum. The antibodies may also be assayed by the ability of the test serum to stimulate cyclic AMP in a thyroid slice assay. Hence values are not given in this table. (Reproduced from Laurberg et al. [21], with permission of the Society of the European Journal of Endocrinology. ATD: Anti-thyroid drug; TSH: Thyroid-stimulating hormone.
Outcome of poorly treated or untreated
Graves' hyperthyroidism in pregnancy
Prompt diagnosis and treatment are essential to avoid both maternal and fetal complications. Maternal complications include miscarriage, placenta abruptio and preterm delivery. Congestive heart failure and thyroid storm may also occur and the risk of pregnancy-induced hypertension and pre-eclampsia is significantly higher in women with poorly controlled hyperthyroidism. From the fetal aspect, hyperthyroidism, neonatal hyperthyroidism, prematurity and intrauterine growth retardation may be observed. Hamburger cited 11 reports that collectively documented a 5.6% incidence of fetal death or stillbirth in 249 pregnancies and a further 5% fetal and neonatal abnormalities [17]. These figures are greater than those expected in normal pregnancy. However, many of these reports are relatively old. With better recognition of the treatment requirements of the pregnant Graves' patient these complications should become less frequent. A recent confirmation of the occurrence of fetal loss associated with excess thyroid hormone exposure was provided by Anselmo and colleagues who studied this problem in patients with thyroid hormone resistance thereby avoiding any consideration of thyroid autoimmunity [18]. Miscarriage rates were 22.9% in response to greatly elevated thyroid hormone levels in the affected mother when the fetus did not have this resistance compared with 2–4% in controls. There is therefore no doubt that hyperthyroidism should be treated although it is true to state that Graves' disease may ameliorate during gestation in a similar fashion to other autoimmune diseases.
This gestational amelioration is often associated with a reduction in titer of TSHRAb and, as has been stated, a change from stimulatory to blocking antibody activity is observed in Graves' disease during pregnancy in some cases [19]. It should also be noted that a variety of thyroid-related antibodies may occur in patients with Graves' disease. Zakarij and colleagues, for example, reported the presence of two species of stimulating antibody in a patient who gave birth to three children with transient neonatal hyperthyroidism [20]. In addition to the classical TSHRAb another stimulating antibody whose in vitro stimulating activity was not inhibited by TSH binding inhibitory antibody (TBIAb) was found. In addition, this particular patient also had appreciable amounts of TBIAb. This report emphasizes the concept that patients with Graves' hyperthyroidism often possess more than one antibody directed against the TSHR. To emphasize this, a recent report has documented the appearance of a blocking antibody to TSHR which was suggested to be the cause of the development of primary hypothyroidism in a patient with Graves' disease in late pregnancy [21].
Management
Preconception
There is a good case for a preconception clinic for patients with Graves' hyperthyroidism who wish to become pregnant. First, education about the effects of the disease on maternal health and fetal well-being can be given to allay fears that are commonly present in these women. The patient's thyroid status should be checked frequently to minimize risk of miscarriage should she be hyperthyroid at the time of conception. If treatment had commenced with methimazole or carbimazole, a change to propylthiouracil (PTU) is recommended to reduce the admittedly rare occurrence of aplasia cutis reported following the administration of the former drugs as well as the rarer and more serious embryopathy [22]. The management of the patient during gestation shall be discussed below.
Previously treated patients with Graves' disease
These patients may have received anti-thyroid drugs, surgery or radioiodine therapy and be euthyroid on or off thyroxine therapy. The important concern here is that fetal and neonatal hyperthyroidism may still occur. Recent guidelines state that if antithyoid drugs have been previously used there is no need to measure TSHRAbs as the maternal thyroid function gives a reliable estimate of fetal thyroid status and the risk of neonatal hyperthyroidism is very low [23] (Table 3). TSHRAbs should be measured in a euthyroid pregnant woman previously treated by either of the other modalities early in pregnancy. If the level is high at this time the fetus should be evaluated carefully during gestation and the antibodies measured again in the last trimester (Box 1). In women with active Graves' disease umbilical blood sampling may improve the control of fetal thyroid function in selected cases [24] but this procedure has to be balanced against the potential risk.
Graves' hyperthyroidism inadvertently treated with radioiodine in early gestation
The practical procedures surrounding the administration of radioiodine therapy for Graves' disease vary widely. In many clinics routine pregnancy testing is not performed before 131I administration. Despite patient denial of pregnancy, several reports of inappropriate radioiodine administration have highlighted the concern about fetal radiation risk [25]. The maternal thyroid uptake, the gestational age and the ability of the fetal thyroid to concentrate iodine are all vital in determining the radioiodine exposure in utero. The fetal thyroid concentrates iodide after 10 to 12 weeks gestation and is relatively more avid for iodine than the maternal thyroid. The fetal tissues are also more radio-sensitive. Administration of up to 15 mci (555 MBq)131I for hyperthyroidism up to 10 weeks gestation does not compromise fetal thyroid function and the low fetal whole-body irradiation is not considered sufficient to justify termination of pregnancy, although this is often performed. However, from limited clinical data, 131I given after that gestational age results in biochemical hypothyroidism and even cretinism in the neonate [26]. In these circumstances termination of pregnancy may be advised but dosimetry studies should be performed. If the pregnancy continues to term, intrauterine hypothyroidism may be diagnosed by umbilical cord sampling. The neonate should be evaluated at birth specifically for hypothyroidism and for malformations, which are more common with higher doses of radiation. Nevertheless some experience even with high administered activity of radioiodine in the second trimester suggests that the total absorbed dose to the fetal body did not justify termination of pregnancy [27].
Patients found to have hyperthyroid Graves' disease in early pregnancy
Medical therapy is preferred by most clinicians as radioiodine is contraindicated and surgery requires pretreatment with anti-thyroid drugs to render the patient euthyroid. When there is not a combined antenatal clinic with an obstetrician together with a physician skilled in management of patients with thyroid disorders, patients are usually treated by obstetricians, although there is concern that some feel their training to be inadequate with low confidence in managing the condition [28]. It may not be appropriate for obstetricians to be managing Graves' disease in pregnancy. Treatment is essential to minimize the adverse outcomes associated with Graves' disease. General management is outlined in Box 1. PTU should be given in a dose of 100–150 mg three-times daily until the patient becomes euthyroid (with normal thyroid function tests) at which time the dose should be reduced to the lowest amount to maintain the euthyroid state. The preference for PTU rather than methimazole (or carbimazole) administration relates firstly to the occurrence of aplasia cutis with methimazole but not with PTU [29]. Second, the incidence of methimazole embryopathy (a severe midline deformity characterized by choanal atresia and facial abnormalities), although rare, can be devastating [30]. There is only one reported case resulting from PTU administration [31] and many clinicians feel that PTU is the preferred drug. However, in terms of rapidity of action and potential to induce fetal hypothyroidism, there is probably little reason to choose PTU over methimazole. The so-called ‘block and replace’ regimen in which thyroxine is given with an anti-thyroid drug should not be used because the dose of anti-thyroid drug would inevitably be too high and cause fetal goiter and hypothyroidism. The aim of treatment should be to maintain the serum T4 concentration at the upper end of the normal range for pregnancy. T4 administration to pregnant women with Graves' hyperthyroidism during pregnancy and after delivery, together with methimazole, was claimed to be effective in reducing the incidence of postpartum recurrence of hyperthyroidism but these results have not been confirmed. PTU should be continued at a low dose throughout gestation and up to, and through labor, although some clinicians stop the drug before delivery. Common complications of thionamide therapy include skin rash, arthralgia and nausea in about 2% of patients. Methimazole (or carbimazole) may be used as an alternative in this situation with only a 33% chance of crossreaction. Agranulocytosis is rare and is an indication for immediate withdrawal of the drug and possible treatment with granulocyte colony-stimulating factor, although the results are not always satisfactory in non-pregnant patients; it has not been used in pregnant patients. There is no benefit in routine monitoring of the white blood count as the fall in whole blood count may be very rapid. β-adrenergic blocking agents such as propranolol may be used for a few weeks to ameliorate the peripheral sympathomimetic actions of excess thyroid hormone but prolonged use can result in retarded fetal growth and impaired response to anoxic stress together with postnatal bradycardia and hypoglycemia.
Management of Graves' hyperthyroidism in pregnancy
Confirm diagnosis.
Start propylthiouracil.
Render patient euthyroid; continue with low-dose anti-thyroid drug (ATD) up to and during labor.
Monitor thyroid function regularly throughout gestation (4–6 weekly) adjust ATD if necessary.
Check thydroid-stimulating hormone receptor antibodies at 36 weeks'gestation.
Discuss treatment with patient.
Effect on patient.
Effect on fetus.
Breastfeeding.
Inform obstetrician and pediatrician.
Check infant for thyroid dysfunction if indicated.
Review postpartum – check for exacerbation.
Fetal evaluation
As indicated, the fetus is at risk of thyroid dysfunction if the mother has TSH receptor antibodies and/or is taking anti-thyroid drugs during the third trimester. Demonstration of fetal goiter by ultrasonography is an important predictor of fetal thyroid dysfunction. It has been reported that fetal thyroid function is normal if there is no goiter but fetal hyperthyroidism or hypothyroidism may be diagnosed if there is thyroid enlargement [32]. Fetal hypothyroidism is seen in mothers taking anti-thyroid drugs. Further fetal thyroid status evaluation may be obtained from an estimate of bone maturation at the distal femoral center and fetal heart rate as well as fetal growth. Fetal blood sampling should be reserved for those cases in which fetal hypothyroidism requires intra-amniotic injection of levothyroxine or where doubt exists between fetal hyper- and hypothyroidism.
Lactation & thyrotoxicosis
Available evidence suggests that there is no significant effect of anti-thyroid drugs in utero on the long-term health of the neonate or child assuming the dose during gestation has not caused iatrogenic fetal hypothyroidism. PTU has a shorter half-life than methimazole and is more bound to serum proteins; hence it is not present in as high a concentration in breast milk. Women receiving PTU can breast-feed without significant risk to the neonate [33,34]. In addition, comprehensive studies have shown that thyroid function and physical and intellectual development of breast-fed infants up to 86 months is not affected by maternal methimazole therapy [35,36], even if the mothers had developed hypothyroidism due to drug therapy [37]. The overall conclusions from these and other studies are encouraging and suggest that with maternal doses of up to PTU 750 mg or methimazole 20 mg (or equivalent) there are no significant alterations in neonatal thyroid hormone concentrations.
Other causes of hyperthyroidism
Hyperemesis gravidarum is common and around 5% of cases require hospital admission because of dehydration and ketosis. The syndrome of transient hyperthyroidism of hyperemesis gravidarum should be considered in any woman presenting with biochemical evidence of hyperthyroidism in early pregnancy. Thyroid function should be checked in these patients; a correlation has been established between the severity of the hyperemesis and thyroid function with an elevated FT4 and FT3 with suppressed TSH. The FT3 may be normal in a patient with poor nutrition presumably due to reduced T4 to T3 conversion. In those patients who are hyperthyroid anti-thyroid drugs may be given, although the hyperthyroidism is self-limiting and usually disappears with the cessation of vomiting. The diagnosis of gestational thyrotoxicosis will be confirmed by noting the absence of TSHR-stimulating antibodies, negative anti-TPO antibodies, usually an absence of goiter and circulating hCG with high biologic activity. As noted, a woman with low TSH in the first trimester is almost certainly not hyperthyroid, especially if the FT4 and FT3 are normal. The TSH concentration falls as a normal physiologic response to the increase in hCG between 8 and 12 weeks gestation. Hence no further investigation is required if thyroid hormone concentrations are normal.
With regard to toxic multinodular goiter and toxic adenoma, radioiodine, which may be the treatment of choice, is absolutely contraindicated in pregnancy. The conditions may be managed with anti-thyroid drugs during gestation; if necessary surgery may be performed during the second trimester but if possible it is better to postpone this till the postpartum period.
The diagnosis of subacute thyroiditis is suggested by the presentation of a painful thyroid in the presence of hyperthyroidism. As radionuclide evaluation (which would demonstrate a low iodine uptake) is contraindicated, diagnosis may be made with a fine needle aspiration biopsy of the thyroid associated with an elevation in systemic markers of inflammation. Treatment is firstly with analgesics for pain and oral predinosolone therapy if inflammation is severe. Frequent monitoring of thyroid function is required as a small number of patients will develop hypothyroidism.
Surgery
Subtotal thyroidectomy is indicated if control of the hyperthyroidism is poor on account of poor compliance or inability to take drugs. Patients with a very large goiter may also require surgery because of pressure symptoms. Surgery is preferred in the second trimester as there is a higher risk of associated abortion at an earlier stage of gestation. In general, surgery should be avoided if it is considered that medical therapy has a reasonable chance of success.
Severe hyperthyroidism
This refers to patients who have been non-compliant with previously prescribed drug therapy as well as patients presenting for the first time late in gestation with severe hyperthyroidism. Rarely, an episode of infection or the development of pre-eclampsia may precipitate thyroid storm. This is a medical emergency requiring the use of thionamides, iodides, β-blockers, fluid replacement and possibly steroid therapy and plasmapheresis to achieve euthyroidism [35].
Postpartum Graves' disease
Patients with Graves' disease may develop Graves' hyperthyroidism during the early postpartum period. Occasionally this is followed immediately by transient hypothyroidism due to co-existing destructive autoimmune thyroiditis despite increasing TSHRAb activity [39]. This may be important when considering postpartum relapse of the disease.
The pathogenesis is related to what is know as ‘immune rebound phenomenon’ in which the immune system, depressed during gestation, becomes activated postpartum with an accompanying elevation of thyroid antibodies. TSHRAbs tend to decrease during late gestation in Graves' disease patients but there is a significant rebound in the early postpartum period. Individual patients at high risk of postpartum onset of Graves' disease can be found in early pregnancy by the detection of TSHRAb and up to 40% of women of child-bearing age may have developed their disease during the postpartum period.
It is important to differentiate postpartum Graves' disease with accompanying hyperthyroidism from postpartum thyroiditis with hyperthyroidism [40]. PPT occurs almost exclusively in women who are found to have circulating anti-TPO antibodies in early gestation. The presentation of the hyperthyroid phase is at around 13 weeks post partum. Treatment of this destructive thyroiditis is usually not necessary (anti-thyroid drugs would not be helpful), but if tachycardia or palpitations are significant β-adrenoreceptor blocker therapy may be given. The condition spontaneously resolves in 1–4 weeks but may be followed by a hypothyroid phase. The presence of circulating TSHRAb, radioiodine uptake, together with clinical examination and thyroid scintiscanning will usually resolve any diagnostic difficulty although the two conditions may occur together. Radioiodine uptake testing is contraindicated during breast feeding. Prevention of postpartum Graves' hyperthyroidism may be achieved by adequate treatment of the condition before the onset of gestation, which, in some cases, may include destructive therapy.
Future perspective
The improvement in the management of thyrotoxicosis in pregnancy, particularly that due to Graves' disease, over the next decade will depend on:
Refinements in the ability to accurately assess thyroid function during gestation
Exploration of the possibility of maternal thyroid function screening in early gestation if this becomes cost effective
Further elucidation of the immunology of Graves' disease with emphasis on the TSH receptor and its interaction with stimulating antibodies and artificial designer compounds. This will provide a rational immunologic therapy for the condition instead of merely a blocking agent with modest immunosuppressive characteristics.
Executive summary
Graves' hyperthyroidism occurs in up to 2/1000 pregnancies.
Thyroid hormone changes during gestation are due to an increase in thyroxine binding globulin (TBG) and the action of human chorionic gonadotropin.
There is a general immune suppression during pregnancy with an abrupt switch to the prepregnant state after delivery.
The main cause of hyperthyroidism in pregnancy is Graves' disease. Other important causes include hyperemesis gravidarum, associated with gestational transient hyperthyroidism.
Diagnosis of Graves' disease is made clinically and by assay of thyrotropin receptor antibodies if necessary.
Untreated or poorly treated Graves' disease results in an increase in miscarriage, fetal death and neonatal abnormalities.
Management of Graves' hyperthyroidism in pregnancy should ideally be with propylthiouracil. Thyroid-stimulating hormone receptor antibodies should be measured to predict neonatal hypothyroidism.
Radioiodine therapy is totally contraindicated. If inadvertently administered in early gestation, termination is not indicated. If given later, fetal and neonatal hypothyroidism should be carefully checked.
There is a risk of exacerbation of Graves' hypothyroidism in the postpartum period.
Postpartum thyroiditis with a destructive hyperthyroidism occurs in 5–9% of women with positive anti-thyroid peroxidase antibodies.