Hyperthyroidism in pregnancy

Thyroid disease is the second most common endocrine disorder affecting women of reproductive age and when untreated during pregnancy is associated with an increased risk of miscarriage, placental abruption, hypertensive disorders and growth restriction. More common is relapse of previously controlled hyperthyroidism.

Pre-pregnancy hyperthyroidism counselling

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 six months later, once the levothyroxine dose has been optimised).

• Thyroid-stimulating hormone (TSH) levels should ideally be less than 2.5 mIU/L in those women taking levothyroxine prior to conception¹.

• 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.

• Propylthiouracil is less likely to cross the placenta than carbimazole and is usually considered the preferred antithyroid drug. The safest option is often to use propylthiouracil in early pregnancy, changing to carbimazole in the latter months.

• Close follow-up during pregnancy, with TSH receptor antibody (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 breastfeeding.

Changes in thyroid physiology during pregnancy

• Thyroid gland enlargement.

• Increased gland vascularity.

These changes reverse postnatally.

Epidemiology

• It occurs in around 2 per 1,000 pregnancies in the UK.

• The most common cause is Graves' hyperthyroidism - overactivity resulting from the presence of TRAb.

• New-onset hyperthyroidism is estimated to occur in about 0.1-0.4% of pregnancies².

• This may rise to 1% if subclinical hyperthyroidism is included³.

• Transient gestational hyperthyroidism may also occur - it has a 2-3% prevalence in Europe but is much higher in South Asians.

Transient gestational hyperthyroidism

• Associated with hyperemesis gravidarum.

• Can 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.

Postpartum thyroiditis

• Postpartum thyroiditis is defined as an abnormal TSH level within the first 12 months postpartum in the absence of a toxic thyroid nodule or thyrotoxin receptor antibodies⁴.

• Women with a history of type 1 diabetes and women with thyroglobulin or thyroperoxidase autoantibodies are at increased risk of postpartum thyroiditis⁵.

• A radioactive iodine uptake scan can help distinguish postpartum thyroiditis from Graves' disease but is contra-indicated in breastfeeding women.

• Around a quarter of patients present with symptoms of hyperthyroidism, followed by hypothyroidism and then recovery; around one third present with hyperthyroidism; the remainder present with hypothyroidism

• The hyperthyroid phase of postpartum thyroiditis is caused by autoimmune destruction of the thyroid, resulting in release of stored thyroid hormone. This means that antithyroid medications are not typically beneficial and treatment is generally symptomatic, using beta-blockers⁶.

• Women with a history of postpartum thyroiditis are at increased risk of permanent hypothyroidism and should be screened annually thereafter.

Presentation

See the separate Hyperthyroidism article 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

• The differential diagnosis of Graves' hyperthyroidism and transient self-limiting hyperthyroidism in early pregnancy can be difficult, especially since accurate measurement of serum thyroid hormones can be problematic⁶.

• 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).

• Deterioration in the clinical features of Graves' disease in the first trimester of pregnancy may occur due to stimulation of the thyroid both by hCG and thyrotropin receptor-stimulating antibodies. However, an improvement in Graves' disease may occur in the second half of gestation due to the falling titre of thyroid-stimulating antibodies¹.

It is important to remember that the ranges of TSH, T3 and T4 are different in pregnancy.

TSH - levels are trimester-dependent

• Serum free T4 levels during pregnancy should be interpreted with caution

• Each laboratory should establish trimester-specific reference ranges for pregnant women if using a free T4 assay

• It is recommended that the non-pregnant total T4 range (5-12 μg/dL or 50-150 nmol/L) can be adapted in the second and third trimesters by multiplying this range by 1.5-fold.

• Alternatively, the free T4 index ('adjusted T4') can be a reliable assay during pregnancy.

TSH receptor antibody (TRAb)

This can cross the placenta, stimulating the fetal thyroid, so it is important to measure during pregnancy⁷.

• Normal values <130% (by measuring thyroid-stimulating immunoglobulins) of basal activity.

• Risk of fetal or neonatal hyperthyroidism is increased when >500% activity is detected.

• Those women with high antibody concentrations in pregnancy, at diagnosis and at 22-26 weeks of gestation, will usually need to have fetal and neonatal monitoring of thyroid size and function undertaken⁶.

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

Complications

Poorly controlled hyperthyroidism during pregnancy is associated with the following:

Maternal

• Pregnancy-induced hypertension.

• Pre-eclampsia.

• Cardiac failure.

• Premature labour.

• Thyroid storm.

Fetal/neonatal

• High miscarriage rate is associated with high thyroid hormone and thyrotrophin hormone levels (ie not due to autoimmunity).

• Intrauterine growth restriction.

• Low birth-weight baby.

• Stillbirth.

• Thyroid dysfunction.

Subclinical hyperthyroidism can be associated with gestational diabetes⁸⁹. Apart from this it has not been associated with any other adverse effects during pregnancy.

Management¹⁰¹¹¹²

NB: 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 radio-iodine 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.

• Radio-iodine is contra-indicated because of the risk that fetal hypothyroidism could be induced.

• 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.

• 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.

• 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 breastfeeding¹². However, liver toxicity has been recently reported. Current opinion favours using propylthiouracil in early pregnancy and carbimazole in later months¹³.

• 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.

• Because maternal T4 crosses the placenta less well than antithyroid drugs, the block and replace regimen is contra-indicated in pregnancy.⁶

• Medications need to continue into labour.

• As antithyroid drugs may cause neonatal hypothyroidism, a minimal dose required should be used and thyroid hormones should be kept within the upper third of the normal range.

• Graves' disease tends to enter remission as pregnancy proceeds, so doses can usually be reduced or withdrawn in the third trimester⁶.

• Monitoring usually involves the following:
  

  • Measure TFTs every two weeks until the patient is on a stable medication dose and then weekly after 32-34 weeks of gestation in those with poorly controlled hyperthyroidism.

  • Serial fetal ultrasonography (looking for intrauterine growth restriction, hydrops fetalis, advanced bone age, goitre, tachycardia and heart failure).

  • Check TRAb at the end of the second trimester.

Postpartum

• Patients may continue to breastfeed, as 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.

• Interestingly, while universal screening versus case finding for thyroid dysfunction has been shown to increase diagnosis and subsequent treatment, studies have not shown any clear differences for primary outcomes of pre-eclampsia or preterm birth or for secondary outcomes, including miscarriage and fetal or neonatal death¹⁴.