Thyroid disease is a common disorder in pregnancy. In this article the authors, look at the manifestations, management and treatment options
Dr Genevieve Baragwanath,
Professor Bijay Vaidya
Royal Devon & Exeter NHS Foundation Trust
Thyroid disease is common in women of childbearing age and thyroid disorders may first manifest during pregnancy. As symptoms of thyroid disease can simulate those of pregnancy, the diagnosis can be challenging. Thyroid disorders in pregnant women are associated with an increased risk of maternal and fetal complications, and require tailored care to ensure an optimum outcome. This article aims to give an overview of the management of common thyroid disorders in the perinatal period.
How does pregnancy affect thyroid function?
Pregnancy has a number of significant effects on the normal thyroid physiology. Firstly, there is an increased synthesis of thyroxine binding globulin (a plasma protein that binds to thyroid hormones in circulation) by the liver in response to high levels of oestrogen in pregnancy. This results in high serum concentrations of total thyroxine (T4) and triiodothyronine (T3), although does not affect free T4 and free T3 concentrations. Secondly, placental human chorionic gonadotrophin (hCG) has a stimulatory effect on the thyroid follicular cells, resulting in an increased secretion of thyroid hormones associated with reciprocal suppression of thyroid stimulating hormone (TSH). This effect of hCG means the reference range for TSH in pregnant women is lower than that in the non-pregnant adult population. Ideally, each laboratory should have assay and trimester specific reference ranges for thyroid function tests in pregnant women. In the absence of these, the recent guidelines from the American Thyroid Association recommend upper reference limit of TSH as 4mIU/L.1 Finally, there is an increased urinary clearance of iodine in pregnancy. As a result, women living in borderline iodine deficient regions may develop clinically significant iodine deficiency causing goitre and thyroid dysfunction during pregnancy.
Hypothyroidism is one of the most common endocrine disorders seen in pregnancy. Overt hypothyroidism (defined as high TSH associated with low free T4) affects 0.3-0.5% of pregnant women, while subclinical hypothyroidism (also known as mild hypothyroidism; defined as high TSH with normal free T4) affects 2-3%. The most common cause of hypothyroidism in the UK is chronic autoimmune thyroiditis, followed by previous ablative radioactive iodine treatment or thyroidectomy, thyroiditis and drugs. Worldwide, iodine deficiency remains an important cause. About 2% of pregnant women have isolated hypothyroxinaemia (defined as normal TSH with low free T4), the aetiology of which remains uncertain, although iodine deficiency has been implicated in some cases. It is also controversial whether isolated hypothyroxinaemia causes adverse effects, and currently treatment with levothyroxine is not recommended.1
Thyroid hormone is important for neurological development of the fetus; however, fetal thyroid starts functioning only after 12-14 weeks of gestation. Therefore, during early pregnancy, the fetus relies on maternal thyroid hormone for its development.
Multiple studies over the years have shown that both overt and subclinical hypothyroidism in pregnancy is associated with impaired neuropsychological development of the offspring.2 Furthermore, overt and subclinical maternal hypothyroidism also increases the risk of several obstetric complications. For example, a recent study of the UK general practice research database found that increasing TSH levels above 2.5mIU/l in the first trimester is associated with an increasing risk of miscarriage.3 This study also revealed that over 50% pregnant women taking levothyroxine for hypothyroidism have at least one TSH measurement above the recommended limit of 2.5mIU/l in the first trimester, highlighting the need for improvement in the care of pregnant women with hypothyroidism in the UK.
All pregnant women with overt and subclinical hypothyroidism should be treated with levothyroxine replacement. In case of new diagnosis of overt hypothyroidism in pregnancy, full dose of levothyroxine (2μg/kg body weight) should be started promptly. Use a smaller initiating dose of levothyroxine (for example, 50-75μg daily) in newly diagnosed subclinical hypothyroidism. Most women with pre-existing hypothyroidism need to increase the dose of levothyroxine when pregnant to maintain euthyroidism, and this increase in thyroid hormone requirement occurs as early as four weeks of gestation.4 Therefore, women with pre-existing hypothyroidism should ideally optimise levothyroxine dose before conception to keep TSH <2.5mIU/l, and once pregnancy is confirmed, increase the levothyroxine dose by 25-30%. Thyroid function should be monitored at regular interval, during pregnancy to adjust the dose of levothyroxine with an aim to keep serum TSH within the trimester specific reference range. Following delivery, women should reduce the dose of levothyroxine to pre-pregnancy dose. For women who started levothyroxine for subclinical hypothyroidism diagnosed during pregnancy, it is prudent to reassess whether the treatment is still required following delivery by rechecking thyroid function after a trial off levothyroxine.5
Thyroid autoimmunity with normal thyroid function
About 10% of pregnant women are positive for thyroid peroxidase or thyroglobulin antibodies. In addition to an increased risk of hypothyroidism, these women also have a higher incidence of obstetric complications, such as miscarriage and premature birth. Whether levothyroxine reduces these adverse outcomes in these women remains uncertain, and currently a routine treatment with levothyroxine in these women is not recommended.1
Adequate iodine intake is essential for normal thyroid hormone synthesis. It has been known for over a century that severe iodine deficiency causes endemic goitre, hypothyroidism, miscarriage, fetal mortality and cretinism. Recently, it has been shown that even mild-moderate iodine deficiency during pregnancy is associated with reduced IQ in the offspring.6 Furthermore, contrary to the general belief that dietary iodine intake in the UK is adequate, a recent survey has shown that the UK has mild iodine deficiency.7
The recommended daily iodine intake for women of childbearing age is 150μg/day, and this increases to 250μg/day during pregnancy and while breastfeeding.1 Dietary sources of iodine include milk, seafood, eggs, meat, poultry and iodized salt. Several, but not all, prenatal multivitamins also contain 140-150μg iodine.
The two most common causes of thyrotoxicosis in pregnancy are transient gestational hyperthyroidism and Graves’ disease. Other causes, including toxic multinodular goitre, toxic thyroid nodule, thyroiditis and drugs, are rare.
Transient gestational hyperthyroidism, which affects 1-3% of pregnancies, is limited to the first half of pregnancy. It is caused by stimulation of thyroid follicular cells by placental hCG, which peaks at 7-11 weeks of gestation. As women with hyperemesis gravidarum tend to have high levels of hCG, they are at an increased risk. Transient gestational hyperthyroidism often presents with mild thyrotoxicosis (a raised serum free T4 and suppressed TSH) without evidence for thyroid autoimmunity, such as thyroid eye disease or TSH receptor antibodies.
Only a small percentage of affected women have symptoms of thyrotoxicosis and may need a short course of beta blockers for symptom control. Transient gestational hyperthyroidism remits spontaneously by 18-20 weeks of gestation, and a routine use of antithyroid drugs is not recommended for its treatment.1
Graves’ disease (autoimmune hyperthyroidism) affects about 1 in 500 pregnant women. Its symptoms, including heat intolerance, sweating, palpitations, weight loss and tremor, may be confused with those of pregnancy. Women with Graves’ disease often present with a diffuse goitre and occasionally have thyroid eye disease. Diagnosis is made on the basis of biochemical thyrotoxicosis (elevated serum free T4 or free T3 with a suppressed serum TSH) associated with evidence of thyroid autoimmunity (positive TSH receptor antibodies and/or presence of thyroid eye disease).
If a woman with pre-existing Graves’ disease becomes pregnant, the condition may exacerbate in the first trimester but generally improves throughout the rest of the pregnancy.
Graves’ disease in pregnancy is associated with severe adverse effects for mother and fetus, and optimal treatment can prevent these adverse effects. Radioiodine is absolutely contra-indicated in pregnancy and thyroidectomy has a limited use as it carries an increased risk of complications in pregnant women as compared to non-pregnant adults. Therefore, anti-thyroid drugs are the mainstay of treatment of Graves’ disease in pregnancy.
Two anti-thyroid drugs available in the UK are carbimazole and propylthiouracil. Methimazole, which is an active metabolite of carbimazole, is used in some countries.
All anti-thyroid drugs cross the placenta, and therefore carry a risk of embryopathy as well as fetal hypothyroidism and goitre. Carbimazole (and methimazole) use in early pregnancy is associated with a rare but severe embryopathy (including choanal atresia, trachea-oesophageal fistula, aplasia cutis and cardiovascular malformations).8 Recently, propylthiouracil has also been shown to be associated with congenital malformations, although these appear to be less severe than those associated with carbimazole.9 The highest risk period for anti-thyroid drugs associated with congenital malformation is 5-10 of weeks gestation,10 so the need for antithyroid drugs during this critical period should be considered carefully. Furthermore, propylthiouracil is also associated with a rare severe liver toxicity. If antithyroid drugs are needed in the first trimester, current guidelines recommend propylthiouracil.1 It is vital that all young women of reproductive age starting antithyroid drugs are informed of the risk of congenital malformations associated with their use in early pregnancy.
When anti-thyroid drugs are needed in pregnancy, the lowest possible dose should be used to avoid fetal hypothyroidism and goitre. The “block and replace” regime (high dose anti-thyroid drug with levothyroxine) should not be used. Thyroid function needs to be monitored closely (every 4-6 weeks) as the dose of anti-thyroid drug generally decreases throughout pregnancy and about a third will be able to stop the drug altogether. For these women, it is essential to warn them that the risk of recurrence of thyrotoxicosis is high in the postpartum period.
Rarely, Graves’ disease in pregnancy is complicated by fetal or neonatal thyrotoxicosis due to trans-placental transfer of maternal TSH receptor antibodies to the fetus. The presence of TSH receptor antibodies predicts the development of fetal and neonatal thyrotoxicosis, and should be checked in all pregnant women with Graves’ disease1 Women with a history of Graves’ disease previously treated with thyroidectomy or radioiodine may still carry TSH receptor antibodies even if their thyroid function is currently normal. They should also be tested for the antibodies in pregnancy.
Anti-thyroid drugs can be used while breastfeeding; they should be taken in divided doses after feeding. Due to the association of liver toxicity with propylthiouracil, carbimazole is the preferred anti-thyroid drug for lactating women.
The infant’s thyroid function may need to be monitored depending on the dose of anti-thyroid drug (carbimazole >20mg/day, propylthiouracil >300mg/daily).
The management of pregnant women with Graves’ disease is complex, and these women should be promptly referred to secondary care for specialist multi-disciplinary care. In addition, women with Graves’ disease planning pregnancy should also be referred to secondary care.
Postpartum thyroiditis is thyroid dysfunction resulting from inflammation of the thyroid in the first six months after childbirth. Typically, it presents with three phases: transient thyrotoxicosis, hypothyroidism and recovery to euthyroidism. Women with thyroid antibodies (in particular, thyroid peroxidase antibodies) and type 1 diabetes, are particularly at risk of developing post-partum thyroiditis.
Thyrotoxicosis in postpartum thyroiditis is usually mild and resolves spontaneously. Beta blockers can be used for symptom control, but anti-thyroid drugs have no role in the management of post-partum thyroiditis. The hypothyroid phase typically lasts 4-6 months, and levothyroxine can be used for a short period if patients are symptomatic. If levothyroxine is not started, thyroid function should be repeated at 6-8 weekly intervals to check for resolution. Between 20-64% will develop permanent hypothyroidism in the long-term, requiring life-long levothyroxine replacement. Women with postpartum thyroiditis should also be warned that recurrence is likely following future pregnancies.
1. Alexander EK, Pearce EN, Brent GA, et al. 2016 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease during Pregnancy and the Postpartum. Thyroid. 2017 Jan 6. [Epub ahead of print]
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