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 conception.
- 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 anti-thyroid 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.
- Anti-thyroid medication is safe when breast-feeding.
Changes in thyroid physiology during pregnancy
- Thyroid gland enlargement.
- Increased gland vascularity.
These changes reverse postnatally.
- 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 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.
Causes of hyperthyroidism in pregnancy
- Graves' disease.
- Transient gestational hyperthyroidism.
- Toxic multinodular goitre.
- Single toxic adenoma.
- Subacute thyroiditis.
- Iodine-induced hyperthyroidism.
- Struma ovarii.
- Thyrotrophin receptor activation.
Causes of relapse of previously controlled hyperthyroidism during pregnancy
- Increase in TRAb in the first trimester.
- High levels of human chorionic gonadotrophin (hCG) stimulating the thyroid gland.
- Impaired drug absorption through vomiting.
- Labour, infection and caesarean section may also worsen thyroid control.
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.
- Anti-thyroid drugs do not help.
- Resolves as hCG falls.
- 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 antibodies.
- Women with a history of type 1 diabetes and women with thyroglobulin or thyroperoxidase autoantibodies are at increased risk of postpartum thyroiditis.
- A radioactive iodine uptake scan can help distinguish postpartum thyroiditis from Graves' disease but is contra-indicated in breast-feeding 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 anti-thyroid medications are not typically beneficial and treatment is generally symptomatic, using beta-blockers.
- Women with a history of postpartum thyroiditis are at increased risk of permanent hypothyroidism and should be screened annually thereafter.
See separate Hyperthyroidism article for signs and symptoms. However, in pregnancy the following warrant TFTs:
- Heat intolerance.
- Systolic murmur.
- Bowel disturbance.
- Failure to gain weight.
- Emotional upset.
Features of Graves' disease may also be seen - for example:
- Eye signs.
- Weight loss.
- Pretibial myxoedema.
- 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.
- 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 problematic.
- 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 antibodies.
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 pregnancy.
- 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 undertaken.
Thyroid ultrasound scan can be requested but thyroid uptake scans are not recommended.
Poorly controlled hyperthyroidism during pregnancy is associated with the following:
- 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.
- Thyroid dysfunction.
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)
- Anti-thyroid 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 breast-feeding. However, liver toxicity has been recently reported. Current opinion favours using propylthiouracil in early pregnancy and carbimazole in later months.
- 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.
- Because maternal T4 crosses the placenta less well than anti-thyroid drugs, the block and replace regimen is contra-indicated in pregnancy.
- Medications need to continue into labour.
- As anti-thyroid 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 trimester.
- 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.
- Patients may continue to breast-feed, 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 anti-thyroid drugs by this time.
- 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 death.
Further reading and references
Carney LA, Quinlan JD, West JM; Thyroid disease in pregnancy. Am Fam Physician. 2014 Feb 1589(4):273-8.
Pre-conception - advice and management; NICE CKS, June 2012 (UK access only )
Lazarus JH; Pre-conception counselling in graves' disease. Eur Thyroid J. 2012 Apr1(1):24-9. doi: 10.1159/000336102. Epub 2012 Feb 29.
Lazarus JH; Thyroid function in pregnancy. Br Med Bull. 201197:137-48. doi: 10.1093/bmb/ldq039. Epub 2010 Dec 23.
Yalamanchi S, Cooper DS; Thyroid disorders in pregnancy. Curr Opin Obstet Gynecol. 2015 Dec27(6):406-15. doi: 10.1097/GCO.0000000000000226.
Sweeney LB, Stewart C, Gaitonde DY; Thyroiditis: an integrated approach. Am Fam Physician. 2014 Sep 1590(6):389-96.
Groer M, Jevitt C; Symptoms and signs associated with postpartum thyroiditis. J Thyroid Res. 20142014:531969. doi: 10.1155/2014/531969. Epub 2014 Oct 27.
Franklyn JA, Boelaert K; Thyrotoxicosis. Lancet. 2012 Mar 24379(9821):1155-66. doi: 10.1016/S0140-6736(11)60782-4. Epub 2012 Mar 5.
Vandana, Kumar A, Khatuja R, et al; Thyroid dysfunction during pregnancy and in postpartum period: treatment and latest recommendations. Arch Gynecol Obstet. 2014 May289(5):1137-44. doi: 10.1007/s00404-014-3159-y. Epub 2014 Feb 9.
De Groot L, Abalovich M, Alexander EK, et al; Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012 Aug97(8):2543-65. doi: 10.1210/jc.2011-2803.
Bjorgaas MR, Farstad H, Christiansen SC, et al; Impact of Thyrotropin Receptor Antibody Levels on Fetal Development in Two Successive Pregnancies in a Woman with Graves' Disease. Horm Res Paediatr. 2012 Nov 14.
Glinoer D, Cooper DS; The propylthiouracil dilemma. Curr Opin Endocrinol Diabetes Obes. 2012 Oct19(5):402-7. doi: 10.1097/MED.0b013e3283565b49.
Tudela CM, Casey BM, McIntire DD, et al; Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol. 2012 May119(5):983-8. doi: 10.1097/AOG.0b013e318250aeeb.
Parkes IL, Schenker JG, Shufaro Y; Thyroid disorders during pregnancy. Gynecol Endocrinol. 2012 Dec28(12):993-8. doi: 10.3109/09513590.2012.692001. Epub 2012 Jun 12.
Akmal A, Kung J; Propylthiouracil, and methimazole, and carbimazole-related hepatotoxicity. Expert Opin Drug Saf. 2014 Oct13(10):1397-406. doi: 10.1517/14740338.2014.953796. Epub 2014 Aug 26.
Spencer L, Bubner T, Bain E, et al; Screening and subsequent management for thyroid dysfunction pre-pregnancy and during pregnancy for improving maternal and infant health. Cochrane Database Syst Rev. 2015 Sep 219:CD011263. doi: 10.1002/14651858.CD011263.pub2.
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