Management of Graves Hyperthyroidism

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Preconception

There is a good case for a preconception clinic for patients with Graves' hyperthyroidism who wish to become pregnant. Firstly, education about the effects of the disease on maternal health and fetal well-being can be given to

Table 4. Guidelines for measurements of thyroid-stimulating hormone-receptor antibodies in a pregnant woman with Graves' disease (reproduced from Laurberg et al. [37], with permission from the Society of the European Journal of Endocrinology)

Patient status Measurement

Euthyroid - previous ATD not necessary

Euthyroid ± T4 therapy check in early pregnancy: if low or absent no further testing

Previous radioiodine therapy/surgery if high - check fetus and check antibodies in last trimester

Receiving ATD during pregnancy measure in last trimester

ATD = Antithyroid drugs; T4 = thyroxine.

allay fears which are commonly present in these women. The patient's thyroid status should be checked frequently to minimise risk of miscarriage should she be hyperthyroid at the time of conception. If treatment had been commenced with methimazole or carbimazole a change to propylthiouracil (PTU) is recommended to reduce the admittedly rare occurrence of aplasia cutis [35] and the equally rare methimazole embryopathy [36] reported following the administration of the former drugs. The patient may have been rendered euthyroid by partial thyroidectomy or radioiodine therapy. However, if these procedures are performed the patient may require thyroxine therapy (with a requirement for an increase in dose and monitoring during gestation); in addition, there is still a small risk of neonatal hyperthyroidism even if the mother is euthyroid.

Previously Treated Patients with Graves'Disease These patients may have received antithyroid drugs, surgery or radioiodine therapy and be euthyroid on or off thyroxine therapy. The important concern here is that neonatal hyperthyroidism may still occur. Guidelines [37] state that if previous antithyroid drugs alone have been used there is no need to measure TSH receptor antibodies as the maternal thyroid function gives a reliable estimate of fetal thyroid status and the risk of neonatal hyperthyroidism is very low (table 4). TSH receptor antibodies should be measured early in pregnancy in a euthyroid pregnant women previously treated by either of the other modalities. If the level is high (as defined by the local laboratory) at this time the fetus should be evaluated carefully during gestation normally by checking the fetal heart rate and the antibodies measured again in the last trimester (table 4). If there is a detectable titre of stimulating antibodies at 36 weeks the neonate should be checked for hyperthyroidism at birth.

Table S. Management of Graves' hyperthyroidism in pregnancy

Confirm diagnosis Start propylthiouracil

Render patient euthyroid - continue with low dose ATD up to and during labour Monitor thyroid function regularly throughout gestation (4-6 times weekly) - adjust ATD if necessary Check TSAb at 36 weeks of gestation Discuss treatment with patient Effect on patient Effect on fetus Breastfeeding Inform obstetrician and paediatrician Review postpartum - check for exacerbation

ATD = Antithyroid drugs; TSAb = Thyroid-stimulating antibodies.

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 denial of pregnancy several reports of inappropriate radioiodine administration have highlighted the concern about the fetal radiation risk [27]. 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 13-15 weeks of gestation with peak concentrations occurring at 20-24 weeks and is relatively more avid for iodine than the maternal thyroid [38]. The fetal tissues are also more radio-sensitive. Administration of up to 15mCi (555 MBq) 131I for hyperthyroidism up to 10 weeks of gestation does not compromise fetal thyroid function and the low fetal whole body irradiation is not considered sufficient to justify termination of pregnancy. Limited clinical data suggests that 131I given after 10-12 weeks results in biochemical hypothyroidism in the neonate. In these cases management should maintain high normal maternal circulating thyroxine levels and ensure prompt treatment of the neonate with thyroxine. The availability of neonatal screening programmes for congential hypothyroidism ensures that mental retardation can be avoided by appropriate thyroxine treatment.

Patients Found to Have Hyperthyroidism during Pregnancy Medical therapy is preferred by most clinicians as radioiodine is contra-indicated and surgery requires pre-treatment with antithyroid drugs to render the patient euthyroid (table 5).

Propylthiouracil (PTU) should be given in a dose of 100-150 mg three times daily until the patient becomes euthyroid at which time the dose should be reduced to the lowest amount to maintain the euthyroid state with serum T4 at the upper end of normal and continued up to and through labour. PTU is preferred to MMI or carbimazole because there is (in contrast to MMI) no evidence of associated aplasia cutis [39]. There has been a suggestion of a specific methi-mazole embryopathy in children exposed to the drug during the first trimester of pregnancy which, although rare, has not been reported with PTU [36]. As these risks are very small the patient who receives MMI can be normally reassured. In terms of rapidity of action and fetal hypothyroidism inducing potential there is probably little reason to choose PTU over MMI. The so-called 'block and replace' regime in which thyroxine is given with antithyroid drug should not be used because the dose of antithyroid drug would inevitably be too high and cause fetal goitre and hypothyroidism. Hashizume et al. [40] reported that T4 administration to pregnant women with Graves' hyperthyroidism during pregnancy and after delivery, together with methimazole, was effective in reducing the incidence of postpartum recurrence of hyperthyroidism (vide infra) but these results have not been confirmed. Rarely an episode of infection or the development of pre-eclampsia may precipitate thyroid storm requiring the use of thionamides, iodides, beta-blockers, fluid replacement and possibly steroid therapy and plasmapheresis. PTU has a shorter half-life than methimazole and is not present in as high a concentration in breast milk. Hence women receiving PTU can breastfeed without significant risk to the neonate. Common complications of thionamide therapy include skin rash, arthralgia and nausea in about 2% of patients. A vasculitic syndrome may be more common with PTU. Methimazole (or carbimazole) may be used as an alternative in this situation with only a 33% chance of cross-reaction. 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. There is no benefit in routine monitoring of the white blood count as the fall in white blood count may be very rapid, but patients should of course be instructed to report immediately if they develop a sore throat with or without a fever.

There is no significant effect of antithyroid drugs in utero or during breastfeeding on the long-term health of the neonate or child assuming the dose during gestation has not caused iatrogenic fetal hypothyroidism [41]. Beta-adrenergic blocking agents such as propranolol may be used for a few weeks to ameliorate the peripheral sympathomimetic actions of excess thyroid hormone which is usually sufficient for the management of hyperthyroidism; prolonged use may result in retarded fetal growth, impaired response to anoxic stress together with postnatal bradycardia and hypoglycaemia. These drugs will need to be used in the uncommon instance of intolerance to both of the available thionamide drugs. Lithium therapy for hyperthyroidism is contraindicated in pregnancy because of its known teratogenicity.

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