Pre-pregnancy hyperthyroidism counselling^[1]

This should be offered to all women. The main points about which to raise awareness are:

• General pregnancy and pre-conception advice to all women - eg, folic acid.
• Pre-conception patients may be offered definitive therapy - eg, ablation with radiotherapy (ideally, the patient should not conceive until 3-6 months later, once the levothyroxine dose has been optimised).
• Monitor thyroid-stimulating hormone (TSH) and thyrotrophin receptor-stimulating antibodies (TRAb) - they gradually disappear following surgery, whilst with radiotherapy they rise and then usually fall after twelve months.
• Thus, surgery is usually the therapy of choice in women planning to become pregnant.
• Following definitive therapy, levothyroxine dosage may need to be increased early in pregnancy (increased T4 requirement).
• If definitive therapy is not to be considered then the importance of adhering to medication must be stressed, as there is risk of multiple complications, both maternal and fetal.
• Reports from America concerning liver toxicity are being investigated.^[2] Propylthiouracil is, however, less likely to cross the placenta than carbimazole and has been considered the preferred antithyroid drug. These issues should be discussed with the patient. The safest option may be to use propylthiouracil in early pregnancy, changing to carbimazole in the latter months.
• Close follow-up during pregnancy, with TRAb status checked around 24-28 weeks to assess the risk of fetal and/or neonatal hyperthyroidism.
• There is a risk of disease worsening during the first trimester or in the early postpartum period; however, note that women may actually have better control of hyperthyroidism during pregnancy.
• Antithyroid medication is safe when breast-feeding.

Changes in thyroid physiology during pregnancy

• Thyroid gland enlargement.
• Increased gland vascularity.
• These changes reverse postnatally.

Epidemiology^[3]

• It occurs in 2/1,000 pregnancies in the UK.
• The most common cause is Graves' hyperthyroidism - overactivity resulting from the presence of TRAb.
• New-onset Graves' hyperthyroidism is estimated to occur in about 0.15% of pregnancies.
• Transient gestational hyperthyroidism may also occur - it has a 2-3% prevalence in Europe but is much higher in South Asians.

Transient gestational hyperthyroidism^[4]

• Associated with hyperemesis gravidarum.
• Thought to arise from high levels of hCG which stimulate the TSH receptor.
• May occur in molar pregnancy.
• Patients are not usually thyrotoxic.
• Antithyroid drugs do not help.
• Resolves as hCG falls.

Presentation

See separate article Hyperthyroidism for signs and symptoms. However, in pregnancy the following warrant TFTs:

• Tachycardia
• Palpitations
• Heat intolerance
• Systolic murmur
• Bowel disturbance
• Failure to gain weight
• Emotional upset

Features of Graves' disease may also be seen - for example:

• Eye signs
• Tremor
• Weight loss
• Pretibial myxoedema

Differential diagnosis

• Some of the symptoms may be due to pregnancy itself.
• If tachycardia is present then anaemia, arrhythmias and volume depletion might need to be considered.
• More rare causes such as phaeochromocytoma might also need to be considered.

Investigations

Serum TSH can exclude primary thyrotoxicosis. Confirm diagnosis with free T4 levels. If TSH is suppressed but free T4 levels are normal then, if not previously supplied, free T3 level is necessary (T3 toxicosis occurs in 5% of patients). Previously successfully treated Graves' disease is not associated with abnormal TFTs during pregnancy.^[5] It is important to remember that the ranges of TSH, T3 and T4 are different in pregnancy:^[6]

TSH - levels are trimester-dependent

Ranges:^[1]

• 0.2-2.5 mlU/L in the first trimester.
• 0.3-3.0 mlU/L in the second trimester.
• Up to 3.5 mlU/L in the third trimester.

Free T4 varies as albumin and T4-binding globulin change.

TRAb

This can cross the placenta, stimulating the fetal thyroid, so it is important to measure during pregnancy.^[1][7]

• Normal values <130% (by measuring thyroid stimulating immunoglobulins) of basal activity.
• Risk of fetal or neonatal hyperthyroidism is increased when >500% activity is detected.

Thyroid ultrasound scan can be requested but thyroid uptake scans are not recommended.

Complications^[1][3]

Poorly controlled hyperthyroidism during pregnancy is associated with the following:

• Maternal:
  • Pregnancy-induced hypertension.^[8]
  • Pre-eclampsia.
  • Cardiac failure.
  • Premature labour.^[8]
  • Thyroid storm.
  • Placental abruption.
• Fetal/neonatal:
  • High miscarriage rate is associated with high thyroid hormone and thyrotrophin hormone levels (ie not due to autoimmunity).
  • Intrauterine growth restriction.^[8]
  • Low birth-weight baby.^[8]
  • Stillbirth.
  • Thyroid dysfunction.

Subclinical hyperthyroidism can be associated with gestational diabetes.^[2] Apart from this it has not been associated with any other adverse effects during pregnancy.
^[9]

Neonatal hyperthyroidism in Graves' disease^[3]

• Maternal TRAb can decline or alter from stimulatory to inhibitory during pregnancy. Thus, there may be an improvement in hyperthyroidism during pregnancy.
• However, if this does not occur, the maternal TRAb can cross the placenta and stimulate the neonatal thyroid gland. This leads to neonatal hyperthyroidism.
• Neonates develop the following:
  • Intrauterine growth restriction.
  • Tachycardia.
  • Righ heart failure with pleural effusion.^[10]
  • Goitre formation.

Management^[3] [11]

Note: hyperemesis gravidarum is associated with abnormal TFTs which improve once it settles. Control is particularly important as the pregnancy progresses, especially in the third trimester. This is the result of suppression of the fetal pituitary thyroid axis from maternal transfer of thyroxine when hyperthyroidism is poorly controlled. Decide which of the following groups the patient belongs to:

Pregnant mothers with Graves' hyperthyroidism already on treatment or completed treatment

• This includes those on medications or who have had radioiodine or surgery.
• Measure TRAb in the first trimester.
• If TRAb levels are high then there is a need for close monitoring of the fetus, as neonatal hyperthyroidism may occur.
• Monitoring usually involves serial ultrasonography.
• TRAb should be re-measured in the third trimester.
• If TRAb remains high at 36 weeks then the neonate needs to have TFTs performed after birth and then repeated a few days later.

Pregnant mothers with a new diagnosis of hyperthyroidism

• All pregnant women should be referred urgently for assessment of a new diagnosis.

Treatment of all cases of hyperthyroidism during pregnancy (new diagnoses or worsening of previously controlled hyperthyroidism)

• Antithyroid drugs are the first line for all.
• Radioiodine is contra-indicated.
• Surgery is only where absolutely necessary and requires the patient to be rendered euthyroid with drugs to begin with.
• All cases should be discussed with a specialist.
• This needs to be urgently referred if adrenergic symptoms are present which may require treatment.
• Adrenergic symptoms can be treated with short courses of beta-blockers - eg, propranolol. Use beyond a few weeks may adversely affect the fetus and is not advised.
• Antithyroid drugs:
• Propylthiouracil may cross the placenta less readily than carbimazole (which has, on rare occasions, been associated with teratogenic affects) and it is the first choice in pregnancy and breast-feeding. However, liver toxicity has been recently reported (see 'Pre-pregnancy hyperthyroidism counselling', above). Current opinion favours using propylthiouracil in early pregnancy and carbimazole in later months.^[2][13]
• Rarely, carbimazole has been associated with teratogenic affects.
• However, in some countries, carbimazole may be the only choice available and the risks of not treating maternal hyperthyroidism will far outweigh those of potential teratogenicity.
• The aim is to keep the thyroid hormones in the upper third of the reference range. Once this is achieved then the dose of propylthiouracil is decreased to prevent effects on neonatal thyroid function (may produce neonatal hypothyroidism). A similar strategy is used in Graves' disease presenting during pregnancy.
• Block and replace regimen is not recommended and medications need to continue into labour - albeit at a lower dose.
• Remember that antithyroid drugs may cause neonatal hypothyroidism - thus, a minimal dose required should be used and thyroid hormones should be kept within the upper third of the normal range.
• All monitoring of pregnant women should take place in secondary care but a full TFT profile should be sent from primary care. Monitoring usually involves the following:^[14]
  • Measure TFTs every 4-6 weeks.
  • Serial fetal ultrasonography (looking for intrauterine growth restriction, hydrops fetalis, advanced bone age, goitre, tachycardia and heart failure).
  • Check TRAb.

Postpartum^[3]

• Patients may continue to breast-feed - the risk of propylthiouracil and carbimazole being secreted into breast milk is negligible. However, neonatal thyroid function should be checked regularly.
• Measure TFTs in both mother (six weeks and three months) and the neonate (six hours and again a few days later). The reason for rechecking TFTs a few days after birth is that the neonate will have metabolised any maternal antithyroid drugs by this time.

Prognosis

Good thyroid control is associated with a normal pregnancy with good maternal and fetal health, although recent work does suggest it to be an independent risk factor for Caesarean section.^[15]