Course Authors

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.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity 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.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• Describe mechanisms for hyperthyroidism in pregnancy

• Discuss the principles of treatment of hyperthyroidism in pregnancy and breast-feeding

• Discuss the impact of hyperthyroidism on the fetus and neonate.

 

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.

Diagnosis

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.

Mechanisms

Most patients with hyperthyroidism in pregnancy have an autoimmune cause; some additional interesting mechanisms will also be addressed here.

Graves' Disease

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:

1. the physiologic hyperthyroidism of the first trimester, in which TSH is mildly suppressed transiently; but thyroid hormone levels generally remain within the normal range (discussed in an earlier Cyberounds^®). Asian women may be at increased risk for this physiological form of transient hyperthyroidism.
2. hyperemesis gravidarum, defined as nausea and vomiting associated with weight loss of more than 5% during early pregnancy. This has also been identified as a clinical entity that may possibly be associated with thyroid hyperfunction. However, evaluation of thyroid function in studies of severe hyperemesis has not provided uniform results. In earlier studies,(2),(27) high free thyroid hormone concentrations were found in 30-70% of patients with hyperemesis. This elevation of thyroid hormones was thought to be associated with the natural increase in HCG in the first trimester. In other studies,(29) much fewer women have had elevated values.

   It is, therefore, not clear if elevated free hormone is a cause of vomiting in pregnancy or whether the hyperemesis is the result of a direct effect of high HCG and/or estradiol concentrations. Another suggested mechanism is the secretion of a HCG molecule with increased biological activity. Some women with hyperemesis have benefited from therapy with antithyroid agents. Many have either subclinical or mild overt hyperthyroidism, which resolves together with the hyperemesis and rarely requires antithyroid treatment.

3. gestational trophoblastic disease has long been known to cause hyperthyroidism. Amenorrhoeic women with apparent pregnancies, who turn out to have trophoblastic tumors, may have extremely high HCG concentrations and hyperthyroidism occurs in as many as 60% of women with the disease. It is treated by evacuation of the mole or therapy directed against choriocarcinoma. Symptomatic therapy directed at bringing the patient towards a euthyroid state may be necessary.
4. gestational hyperthyroidism with normal HCG concentrations. This is a most unusual variant of HCG-related disease in pregnancy. It was recognized in a patient and her mother who developed recurrent hyperthyroidism of pregnancy, yet were found to be euthyroid when not pregnant.(26) Recurrent hyperthyroidism is unusual. If recurrence in a subsequent pregnancy occurs, it is most likely caused by lack of compliance with intended ablative therapy following an initial hyperthyroid pregnancy, or in a patient on long-term therapy with antithyroid medications who becomes pregnant for a second time. Certainly, one would expect a patient to be hyperthyroid at some time between pregnancies. However, in this particular case, recurrent hyperthyroidism, apparently exclusive to pregnancy, was investigated, leading to the description of an interesting new condition that causes gestational hyperthyroidism.

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.

Fetal Hyperthyroidism

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

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:

1. The overall therapeutic goal is to maintain maternal free thyroid hormone levels at mildly elevated values.

   This goal has developed from information about the mother and the fetus garnered from a series of observational studies. Correlations of fetal and maternal thyroid function have been achieved by evaluating neonatal thyroid function and relating it to maternal levels. Two important findings have impact on management. The first is that hormone levels correlate better with neonatal outcome than do the mother's symptoms. Provided the mother is doing well, hormone levels determine the goals of therapy. The second is that if the mother is euthyroid on treatment, she is more likely to have a hypothyroid neonate. Although this hypothyroidism is usually quite mild, there is great concern at this time about the long-term neuropsychological impact of maternal and also fetal hypothyroidism (see previous Cyberounds^®).(9) Given the tolerance for mild hyperthyroidism in pregnant mothers, this is an achievable goal designed to prevent neonatal hypothyroidism.

   Mothers tolerate mild hyperthyroidism very well during pregnancy, which makes mildly elevated hormone levels a feasible goal. Second, hyperthyroidism tends to ameliorate spontaneously (discussed above). These two facts allow for managing cases of mild hyperthyroidism, even if diagnosed early in pregnancy, with careful observation alone and without pharmacological treatment.

2. Therapeutic goals should be achieved with the lowest dose of thionamides possible.

   Given the transmission of thionamides across the placenta and their potential to cause neonatal hypothyroidism and goitre, this goal fits well with the first. Doses of propylthiouracil (PTU) can begin with 100 mg TID, and increase if necessary, but with the goal of reducing the dose as soon as free hormone levels begin to decrease. However, especially at the onset of treatment, higher doses may be required to get the job done. In severe hyperthyroidism, doses as high as used in the non-pregnant state may have to be used to improve the patient's condition. If high doses are required for prolonged periods, surgical treatment of hyperthyroidism has also been recommended.

   The effect of pregnancy upon pharmacokinetics of thionamides is not well-established. Reports are conflicting as to whether their clearance is increased; if so, higher doses might be necessary and able to be tolerated than in the non-pregnant state. Once doses of 50 to 100 mg per day are achieved, it is often possible to stop therapy altogether in order to minimize the potential for suppression of the fetal gland.

3. Careful follow-up and ongoing communication with the patient's obstetrician.

   Follow-up should occur at four-week intervals if the patient's course is routine, obtaining hormone levels before each visit and adjusting the dose of thionamide based on these values. Frequent follow-up is necessary not only to monitor improvement in the hyperthyroidism but also to prevent hypothyroidism from developing. TSH and free hormone monitoring will allow achievement of the goals of keeping TSH slightly suppressed and free hormone concentrations slightly elevated by dose adjustment of thionamides.

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.

Summary

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.