Hyperthyroidism in Pregnancy
Tricia Westhoff, M.D., and Eli Ipp, M.D.
Dr. Westhoff is Endocrinology Fellow, Harbor-UCLA Medical Center and Dr. Ipp is Professor of Medicine, UCLA School of Medicine.
Dr. Westhoff reports no commercial conflict of interest. In the past three years, Dr. Ipp has received grant/research support from Pfizer, Inc., R.W. Johnson, and Novo-Nordisk. He has served as a consultant for Novo-Nordisk, SmithKline Beecham Pharmaceutical and Hoechst Marion Roussel. Dr Ipp has also served on the Speakers' Bureau for Novo-Nordisk.
Release Date: 09/01/2001
Termination Date: 09/01/2004
Estimated time to complete: 1 hour(s).
Albert Einstein College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Learning ObjectivesUpon completion of this Cyberounds®, you should be able to:
Hyperthyroidism is not a common problem in pregnancy, complicating only in one of 1000-2000 pregnancies. Yet, its appropriate diagnosis and management is of critical importance for the safety and health of both mother and fetus. This Cyberounds® conference will address the differential diagnosis and management of hyperthyroidism in pregnancy and some additional topics, such as neonatal hyperthyroidism and breast feeding in hyperthyroid women.
Risks of Hyperthyroidism in Pregnancy
As was pointed out in the previous Cyberounds®, endocrine disease in pregnancy has potential impact upon mother, fetus and neonate. Risks of management always need to be placed into the perspective of the underlying risk of untreated disease, in this case more than just the mother. Pregnant women with uncontrolled hyperthyroidism are at risk for fetal complications as well as health risks of their own. Low birth weight and prematurity are recognized risks for the fetus of women who have hyperthyroidism in pregnancy. Odds ratios for low birth weight or prematurity were 10 and 16 respectively in one large study, in which women with uncontrolled hyperthyroidism were compared with women who were well controlled before, and throughout pregnancy.(18)
Infants small for gestational age as well as stillbirths have also been described in other studies. It is not clear if untreated Graves' disease is associated with an increase in congenital abnormalities. Studies examining this issue in women who were hypothyroid in the first trimester have revealed conflicting results.(19),(20),(30) If anomalies do occur at increased frequency, it appears to be a small increase only.
Finally, risks for mothers include preeclampsia, eclampsia, and an increased risk for heart failure in untreated patients during pregnancy.
The clinical diagnosis of hyperthyroidism in pregnancy is complicated by the fact that some of the physiological changes of pregnancy mimic symptoms and signs of thyrotoxicosis. Thus, increase in pulse rate, sweating, heat intolerance, mood changes, smooth skin and hair loss may all be reported in euthyroid pregnancies. Mild enlargement of the thyroid gland during pregnancy, particularly in iodine deficient areas was discussed in the previous Cyberounds®. However, severe symptoms, that may include significant weight loss, vomiting, insomnia, hypertension or goiter suggestive of thyroid disease, should be evaluated to rule out thyroid dysfunction. The influence of pregnancy upon thyroid binding proteins and the resulting difficulties in interpretation of thyroid function tests were discussed in the previous Cyberounds®. Diagnosis depends upon obtaining a clinical history and physical examination compatible with hyperthyroidism and biochemical findings of an elevation of free thyroid hormones and a suppressed TSH.
Most patients with hyperthyroidism in pregnancy have an autoimmune cause; some additional interesting mechanisms will also be addressed here.
Graves' disease is the most common cause of hyperthyroidism in pregnancy, as it is in non-pregnant women. Ninety-five percent of hyperthyroidism in pregnancy is accounted for by this autoimmune disease caused by thyroid-stimulating antibodies. In Graves' disease, thyroid-stimulating immunoglobulins (TSI) bind to, and stimulate TSH receptors, resulting in an excess of thyroid hormone secretion.
In any discussion of an autoimmune disease in pregnancy, such as Graves' disease, it is important to keep in mind that, in general, the maternal immune response is suppressed in pregnancy. This is presumably a protective mechanism to prevent rejection of the fetus. This protective effect may apply to women with Graves' disease as well, for we know that preexisting Graves' disease is often ameliorated during pregnancy. A better understanding of this commonly observed event in the hyperthyroidism of pregnancy is now available:
Two general concepts are important in this regard. First, although there is suppression of cell-mediated immune function, there is also preservation or enhancement of humoral immunity in pregnancy. Second, it is now generally accepted that TSH receptor antibodies are heterogeneous, products of different clones of T and B cells that respond to different epitopes (binding sites) on the TSH receptor. TSI levels have been found to decrease during the course of pregnancy, partially explaining clinical improvement. However, it appears that there is more to this phenomenon.
Levels of thyroid stimulation-blocking antibody (TSBAb; measured as inhibition of TSH-stimulated cAMP release) increase in the second and third trimesters.(15) These antibodies interfere with TSH receptor-mediated stimulation of thyroid function. Clinical status correlates with the changes in antibody concentrations. Thus, conversion from stimulating to blocking antibodies is associated with clinical remission of thyrotoxicosis. In the same study, antibody levels were also evaluated in patients whose hyperthyroidism relapsed during the postpartum period. Reciprocal changes in TSI and TSBAb levels were observed in these patients, i.e., after delivery, TSI increased again and TSBAb began to decrease. These reciprocal changes in TSH receptor antibodies may therefore account for amelioration or remission of Graves' disease in pregnancy as well as the postpartum exacerbation of hyperthyroidism frequently observed in these patients.
HCG and Hyperthyroidism
HCG has long been suspected to play a role in physiological thyroid adaptation to pregnancy, as well as in dysfunctional states during pregnancy. For the most part, this results from excessively high HCG concentrations that interact with the TSH receptor in promiscuous fashion. This promiscuity occurs because of the underlying similarity in sequence and structure between TSH and HCG molecules. Though HCG is a weak agonist of the TSH receptor, at sufficiently high levels it can result in thyroid stimulation. HCG is implicated as a possible cause of thyrotoxicosis in pregnancy in a number of ways:
This rare condition is of interest because it illustrates once again the central role of the TSH receptor as the cause of hyperthyroidism, as well as an unusual case of promiscuous action of HCG. Earlier we discussed the role of the TSH receptor and its interaction with antibodies to cause Graves' disease, and how variation in antibodies and their concentrations influence the variable clinical presentation during and after pregnancy. However, in this disorder, no evidence for autoimmune hyperthyroidism was found. Secondly, HCG levels were normal for pregnancy. Rather, it was found that an abnormal TSH receptor could be stimulated by physiologically elevated HCG to cause disease. In this case, a point mutation (resulting in a substitution of arginine for lysine at position 183) in the TSH receptor gene permits the HCG molecule to bind avidly at concentrations seen in pregnancy. Although excessively high HCG levels can cause hyperthyroidism, it requires an altered TSH receptor molecule for this to occur in the presence of the HCG levels seen in normal pregnancies. Thus, this is an example of promiscuous occupation of a receptor that is not a function of greatly elevated hormone levels, as described above. This form of hyperthyroidism, therefore only manifests in pregnancy, may be familial and requires no therapy postpartum.
Other Causes of Hyperthyroidism
Other causes include the usual causes in the non-pregnant state: toxic nodular goiter (Plummer's disease), the hypermetabolic phase of Hashimoto's thyroiditis, thyroiditis and multinodular goitre. As discussed above, these represent only a small number of patients with hyperthyroidism in pregnancy.
Infants born to women with Graves' disease are potentially at risk for neonatal hyperthyroidism, which results from transplacental passage of maternal thyroid stimulating antibodies that have TSH-like activity. Although the effect of these antibodies is usually mild, and antithyroid drugs cross the placenta to counteract their effects, these infants may require several weeks of antithyroid treatment. The half-life of IgG in the neonatal circulation is longer than that of thionamides. These newborns may present with symptoms of hyperthyroidism several days after birth when the drug has been cleared from their circulation but TSI persists. All newborns of mothers with Graves' disease should be carefully monitored for this possibility. Measurement of TSI during pregnancy can be helpful to discern which of these newborns may be at risk for neonatal Graves' disease. TSI measurement should be carried out in pregnant women with hyperthyroidism and even in those who have a more distant history of thyrotoxicosis and are now euthyroid.
Some neonates are antibody negative with mothers who do not have Graves' disease. In this situation, we should consider, once again, the unusual role of the TSH receptor in the genesis of hyperthyroidism. When no evidence is found for autoimmunity in neonatal thyrotoxicosis, a mutation of the TSH receptor gene should be considered. Activating germline mutations that are expressed in constitutive fashion, (and thus in a state of continuous activation) have now been described that cause neonatal hyperthyroidism.(14) Point mutations place the receptor in a permanent state of activation. Antithyroid drugs initially, followed by surgery if necessary at an older age and, possibly, radioiodine ablation should be considered as therapy.
Another rare mechanism that does not require transplacental passage of maternal TSI to cause neonatal hyperthyroidism includes activating mutations of the stimulatory G protein seen in the McCune-Albright syndrome. Fetal hyperthyroidism may manifest with fetal tachycardia (>160 beats/min), goitre, advanced bone age, poor growth and craniosynostosis. Therapy with PTU or methimazole may be used to treat fetuses who have severe tachycardia or very poor growth. Clinical manifestations of neonatal hyperthyroidism include low birth weight, hepatosplenomegaly and abnormalities of the cranium (microcephaly, frontal bossing, triangular face), as well as the more typical features such as tachycardia and goitre.
Management of Hyperthyroidism in Pregnancy
Hyperthyroidism in pregnancy can be managed using the same methods that are used in the non-pregnant state, except for the obvious prohibition on the use of radioiodine. Because of its passage across the placenta, uptake and destruction of the fetal thyroid might occur. Surgery is best performed during the second trimester, when it is safest for the fetus, but is rarely used because medical treatment with thionamides is usually able to control the hyperthyroidism and has little or no risk for the fetus.
Medical treatment with thionamides is a safe and effective therapy for hyperthyroidism during pregnancy. However, this treatment clearly has the potential for causing fetal complications because transplacental passage of thionamides can potentially cause fetal hypothyroidism or goitre. There are, therefore, a number of important principles of therapy to be considered in medical management:
Choice of Thionamides
Thionamides inhibit synthesis of thyroid hormones by blocking iodination of tyrosine residues. PTU also inhibits the peripheral conversion of T4 to T3. Both propylthiouracil (PTU) and methimazole (MMI) are equally effective in treating hyperthyroidism in pregnancy. A review of 185 hyperthyroid patients in pregnancy showed no difference in time to normalization of thyroid function or in the rate of congenital anomalies when MMI was compared to PTU.(30)
Scalp defect is the classic anomaly reported in the use of MMI, though these are always mild and are rarely seen. Early data suggested that PTU may also cross the placenta to a lesser extent than the other drugs and, therefore, PTU tends to be used more commonly in the United States, probably for these reasons. Despite this, MMI and carbimazole are used extensively and routinely as first line therapy in the pregnant and non-pregnant state in Europe and in other countries. Indeed, more recent data suggest that there is probably little difference in the passage of PTU and MMI across the placenta.(22) No long-term neuropsychological effects in children of mothers treated with either PTU or MMI have been observed.(6)
Methimazole dosage begins at 10 to 30 mg/day, divided into two or three daily doses. In patients with moderate or severe hyperthyroidism, beta-blockers may be necessary to deal with adrenergic symptoms, particularly tachycardia. If started, these should be reduced in dosage and stopped as soon as possible, particularly if the patient is being treated in the third trimester, in order not to use these medications close to the time of delivery. Neonates whose mothers were recently treated with beta-blockers are at risk of postnatal bradycardia and hypoglycemia.
Role of Iodides
Nonradioactive inorganic iodide has been used to inhibit the release of T3 and T4 from the thyroid gland. Organic iodides, which also diminish peripheral conversion of T3 from T4, have been used in non-pregnant women with hyperthyroidism but are not recommended in pregnancy. Infants born to mothers treated with prolonged iodide therapy are at risk for development of goitre. Even with organic iodides, small amounts of the inorganic form are released. Iodide therapy of pregnant women is, therefore, indicated only in acute circumstances (thyroid crisis or immediately before delivery or surgical hyroidectomy).
Breast-Feeding and Thionamides
For many years, women were advised not to breast-feed if they were taking thionamides. These recommendations have now changed. The American Academy of Pediatrics does not consider treatment to be absolutely contraindicated in breast-feeding mothers.(1) After pregnancy, doses of thionamides often must be increased because of changes in the TSH receptor antibodies that cause increased thyroid hormone output, as discussed above. From acute (one-dose) studies of thionamide transfer, it has been estimated that a lactating mother treated with 200 mg PTU three times a day would pass 149 µg of PTU to her infant/day. For a 4-kg infant, this is equivalent to a daily dose of 3 mg in a 70-kg adult, which is negligible in terms of affecting thyroid function in the infant. Passage of MMI is 4-7 times higher in acute tests, yet does not appear to affect the infant's thyroid hormone levels significantly during chronic use of doses up to 20 mg/day.(17) The lower levels of PTU in breast milk probably result from the fact that PTU is more protein-bound and is also more ionized in serum than MMI, both factors contributing to less transfer into breast milk. PTU, therefore, tends to be more often used as the thionamide of choice in breast-feeding women.
While hyperthyroidism in pregnancy appears to be managed in optimal fashion on an empirical basis using accumulating information from a few large trials and numerous smaller reports, there still remains much to be learned about many details, including the role of mild transient hypothyroidism in the fetus. However, the vast majority of women with hyperthyroidism in pregnancy can expect a routine pregnancy and delivery if they are carefully followed throughout gestation. When, occasionally, problems occur, this is often in patients who missed early prenatal care or were undiagnosed during pregnancy. Breast-feeding is possible even on thionamides, thus normalizing this aspect of maternity and careful evaluation of the neonate will pick up the transient neonatal hyperthyroidism of Graves' disease and enable it to be managed appropriately.