Hyperthyroidism in Pregnancy

Test, units

Result

Reference range

TSH, mIU/l

<0.02

0.27–4.2

FreeT4, pmol/l

12–22

FreeT3, pmol/l

12.6

3.1–6.8

TRAb, IU/l

7.2

≤0.9

How would you manage this case?

She wants to conceive again soon but this poses risks from uncontrolled thyroid disease in pregnancy. There may be infertility due to anovulation and there is an increased miscarriage rate. She may develop uncontrolled thyrotoxicosis and is at risk of cardiac failure. Very rarely retrosternal extension of a goitre may cause dysphagia or tracheal obstruction, which can be a problem if the patient requires to be intubated.

There are risks to the fetus or neonate from uncontrolled maternal thyrotoxicosis. Miscarriage rates are increased in thyrotoxicosis. Premature delivery may occur, either due to preterm labour if thyrotoxicosis is uncontrolled or there may be iatrogenic prematurity due to concerns about fetal growth and wellbeing or secondary to thyroidectomy in pregnancy. Fetal and neonatal thyrotoxicosis may develop due to TRAb.

Despite her desire to become pregnant you should explain that she must use contraception until she is euthyroid. You need to outline the risks, both to her and to her fetus, of uncontrolled thyroid disease. She should be treated with propylthiouracil (PTU). Once the patient has been rendered euthyroid by a high dose for 4–6 weeks the PTU should be titrated to the minim dose which will maintain her free T4 at the upper limit of the reference range. She could then attempt to conceive again.

She was commenced on PTU using an initial dose of 200 mg twice daily which has been reduced to 50 mg twice daily. She is now 8-weeks pregnant. Her free T4 is 22.1 pmol/l (first-trimester reference range 12.1–19.6). You should adjust the PTU to the minimum dose that will keep her free T4 at or just above the non-pregnant reference range [1]. You could continue to treat her with PTU 50 mg twice daily but you should anticipate that the PTU dose will need to be reduced; therefore you should monitor her TFT closely, every month. PTU infrequently causes severe hepatitic reactions so consider changing to carbimazole or methimazole (CBZ/MMI) after the first trimester when organogenesis is complete; the equivalent dose of carbimazole is 10–15 times less than for PTU. In a patient receiving only a small dose of PTU you could anticipate reducing and stopping it within 2 months. In addition to TFT, liver function tests should be monitored in patients receiving PTU.

Fetal anatomy ultrasound is usually undertaken at 18–20 weeks. In the event that antithyroid medication is continued after 20 weeks gestation or the TRAb is elevated over 4 IU/l (or two to three times the reference range) when rechecked at this stage, then additional growth scans should be arranged every 4–6 weeks or as indicated clinically. Evidence of fetal thyroid dysfunction includes goitre, tachycardia, growth retardation, hydrops and cardiac failure. An alert should be sent to the paediatrician to assess the newborn baby for transient neonatal Graves’ disease.

Whereas Graves’ toxicosis ameliorates during pregnancy you should anticipate a rebound after delivery. You will need to arrange ongoing close endocrine monitoring and should expect to restart or increase antithyroid drugs. Both CBZ/MMI and PTU are secreted in breast milk and borderline elevation of TSH can occur in breastfed infants. CBZ/MMI in doses up to 30 mg daily are preferred to PTU, used in doses up to 300 mg daily, in view of the risk of hepatitis with PTU [2]. Treatment should be taken in divided doses immediately after breastfeeding.

Update of Graves’ Disease Before and During Pregnancy

Antithyroid drugs are the mainstay of treatment. CBZ/MMI would normally be the drugs of first choice to treat Graves’ thyrotoxicosis in the non-pregnant situation. However, in a patient trying to conceive PTU is more appropriate than CBZ/MMI which are teratogenic [1, 3]. Treatment with CBZ/MMI in the first trimester is associated with the congenital skin defect aplasia cutis, and infrequently choanal atresia (posterior nasal passage), oesophageal atresia, omphatocele and omphalomesenteric duct abnormalities. The incidence of aplasia cutis combined with the latter two congenital defects is 1.6 % of patients treated with CBZ/MMI in the first trimester [4]. However CBZ/MMI should be used after 13 weeks gestation for patients requiring continued antithyroid medication or presenting de novo with thyrotoxicosis. Indications for thyroidectomy in pregnancy include severe adverse reactions to antithyroid drugs, ongoing high doses of these medications, for example CBZ/MMI >30 mg per day or PTU >450 mg per day, or inability to control thyrotoxicosis due to compliance issues. If surgery is required, the optimum time is the second trimester. Radioiodine treatment is not used in pregnancy.

It is important to measure TRAb in pregnant women who are hypothyroid following prior radioiodine treatment or in those who had thyroidectomy. Elevated levels may persist and these immunoglobulin G (IgG) antibodies freely cross the placenta and may render the fetus toxic. Conversely in patients who have had prior Graves’ disease in remission, not requiring antithyroid drugs, then fetal growth is not likely to be compromised.

Compared to pre-pregnancy levels total T4 and total T3 are increased in pregnancy, secondary to a rise in thyroid-binding globulin which is caused by an elevation in oestradiol. Conversely free T4 and free T3 show small progressive decreases during the course of pregnancy. These changes depend on the assay used and trimester-specific ranges should be obtained from your local laboratory. TSH falls transiently during the first trimester, mirroring the rise seen for human chorionic gonadotropin (hCG).

Case 2: First-Trimester Hyperthyroidism

A 21-year-old Asian woman presents with frequent vomiting. It is 8 weeks since her last menstrual period and a pregnancy test is positive. This is her first pregnancy. She is unable to tolerate any oral food or fluid and she has been admitted to the local gynaecology unit for hydration and administration of antiemetic. Investigation of thyroid function has shown abnormal results with TSH fully suppressed and free T4 raised 40 % above the first trimester reference range.

What questions should be asked?

Has she had symptoms suggestive of thyrotoxicosis, e.g., heat intolerance, palpitations, emotional lability, weight loss and tremor? If these symptoms have been present did they precede the pregnancy or develop only recently?

Has she previously had thyrotoxicosis and is there a family history of thyroid disease?

Is there a personal or family history of other autoimmune disease?

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