Hyperthyroidism may present as a new diagnosis in pregnancy, affecting up to 0.1-0.4% of pregnancies.¹ More common is relapse of previously controlled hyperthyroidism.

Pre-pregnancy counselling in patients with hyperthyroidism¹

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

• General pregnancy and preconceptual advice to all women, e.g. folic acid.
• Preconception patients may be offered definitive therapy, e.g. 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 receptor antibodies (TRAb) - they gradually disappear following surgery, whilst with radiotherapy they rise and then usually fall after 12 months.
• Thus surgery is usually the therapy of choice in women planning to become pregnant.
• Following definitive therapy levothyroxine dose 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.
• Antithyroid drugs are safe in pregnancy.²
• Close follow-up during pregnancy, with TRAb status checked around 24-28 weeks to assess the risk of fetal and/or neonatal hyperthyroidism (see below)
• There is a risk of disease worsening during the first trimester or in the early postpartum period; however, note that pregnant 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

Epidemiology³

• Occurs in 2/1,000 pregnancies in the UK.
• The most common cause is Graves' hyperthyroidism - overactivity resulting from the presence of thyrotrophin receptor stimulating antibodies (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 hyperthyroidism⁴

• Associated with hyperemesis gravidarum.
• Thought to arise from high levels of hCG which stimulates 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 general Hyperthyroidism article for signs and symptoms. However, in pregnancy the following warrant thyroid function tests (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 suppressed but free T4 levels normal then, if not previously supplied, need free T3 level (T3 toxicosis occurs in 5% of patients). Previously successfully treated Graves' disease is not associated with abnormal TFTs during pregnancy.⁵It 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 milli U/L in 1st trimester
• 0.3-3.0 milli U/L in second trimester
• Up to 3.5 milli U/L in 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

• 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.⁷
  • Pre-eclampsia.
  • Cardiac failure.
  • Premature labour.⁷
  • Thyroid storm.
  • Placental abruption.
• Fetal/neonatal
  • High miscarriage rate is associated with high thyroid hormone and thyrotrophin hormone levels (i.e. not due to autoimmunity).
  • Intrauterine growth retardation.⁷
  • Low birthweight baby.⁷
  • Stillbirth.
  • Thyroid dysfunction.

At present, subclinical hyperthyroidism had not been associated with any adverse effects during pregnancy.^3,8,9

Neonatal hyperthyroidism in Graves' disease³

• 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 retardation
  • Tachycardia
  • Heart failure
  • Goitre formation

Management³

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

• This includes those currently on treatment or who have already completed treatment, e.g. medications, 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 remeasured 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 if 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 if adrenergic symptoms are present which may require treatment.
• Adrenergic symptoms can be treated with short courses of betablockers, e.g. 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 and it is first choice in pregnancy and breast-feeding.^9,11
  • 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 affects 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:^3,9
  • Measure TFTs every 4-6 weeks.
  • Serial fetal ultrasonography (looking for intrauterine growth retardation, hydrops fetalis, advanced bone age, goitre, tachycardia and heart failure).
  • Check TRAb.

Postpartum³

• Patients may continue to breast-feed - the risk of propylthiouracil and carbimazole being secreted into breastmilk is negligible. However, neonatal thyroid function should be checked regularly.
• Measure TFTs in both mother (6 weeks and 3 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.¹²

Document references

1. Patil-Sisodia K, Mestman JH; Graves hyperthyroidism and pregnancy: a clinical update. Endocr Pract. 2010 Jan-Feb;16(1):118-29. [abstract]
2. Rosenfeld H, Ornoy A, Shechtman S, et al; Pregnancy outcome, thyroid dysfunction and fetal goitre after in utero exposure Br J Clin Pharmacol. 2009 Oct;68(4):609-17. [abstract]
3. Marx H, Amin P, Lazarus JH; Hyperthyroidism and pregnancy. BMJ. 2008 Mar 22;336(7645):663-7.
4. Casey BM, Leveno KJ; Thyroid disease in pregnancy. Obstet Gynecol. 2006 Nov;108(5):1283-92. [abstract]
5. Luton D, Le Gac I, Noel M, et al; Thyroid function during pregnancy in women with past Graves' disease. BJOG. 2005 Nov;112(11):1565-7. [abstract]
6. Gartner R; Thyroid diseases in pregnancy. Curr Opin Obstet Gynecol. 2009 Dec;21(6):501-7. [abstract]
7. Luewan S, Chakkabut P, Tongsong T; Outcomes of pregnancy complicated with hyperthyroidism: a cohort study. Arch Gynecol Obstet. 2010 Jan 20. [abstract]
8. Casey BM, Dashe JS, Wells CE, et al; Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol. 2006 Feb;107(2 Pt 1):337-41. [abstract]
9. Abalovich M, Amino N, Barbour LA, et al; Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2007 Aug;92(8 Suppl):S1-47. [abstract]
10. Klein I, Becker DV, Levey GS;Treatment of hyperthyroid disease. Ann Intern Med. 1994 Aug 15;121(4):281-8. [abstract]
11. Mandel SJ, Cooper DS; The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab. 2001 Jun;86(6):2354-9.
12. Pillar N, Levy A, Holcberg G, et al; Pregnancy and perinatal outcome in women with hyperthyroidism. Int J Gynaecol Obstet. 2010 Jan;108(1):61-4. Epub . [abstract]

Acknowledgements