Thyroid Disease During Pregnancy

Options for Management

Tuija Männistö

Disclosures

Expert Rev Endocrinol Metab. 2013;8(6):537-547. 

In This Article

Hyperthyroidism

Hyperthyroidism occurs in 0.1–1.0% of all pregnancies and is diagnosed when TSH concentrations are low or suppressed along with elevated fT4 or free triiodothyronine (in overt disease) or with normal thyroid hormone levels (in subclinical disease).[2] Graves' disease, an autoimmune condition characterized by stimulation of the thyroid gland by TSH receptor antibodies (TRAbs), is the most common cause of hyperthyroidism among fertile-aged women.[2] Other reasons include toxic multinodular goiter, toxic adenoma, thyroiditis or struma ovarii.[2,5] As untreated Graves' disease can lead to ovulatory dysfunction and infertility, a new-onset of Graves' is thought to be rare in pregnancy.[2,5] A more common condition, gestational (transient) hyperthyroidism, occurs in up to 1–3% of all pregnancies and is probably due to the physiologic thyroidal stimulation by high human chorionic gonadotropin levels in early pregnancy.[2,5] Notably, up to 50% of women with hyperemesis gravidarum (severe nausea and vomiting in early pregnancy) have transient hyperthyroidism.[2,5]

Distinguishing between new-onset or recurring Graves' disease in pregnancy and gestational hyperthyroidism may be difficult. Symptoms associated with Graves' disease (goiter or eye symptoms) as well as previous history of thyroid disease help in differentiating between Graves' disease and gestational hyperthyroidism, as gestational hyperthyroidism is more common among women without history of thyroid diseases.[2,5] Elevated TRAb titers are rarely present in gestational hyperthyroidism, so their presence can help confirm Graves' disease in pregnancy.[2,5]

Hyperthyroidism is associated with increased risk of pregnancy complications, including miscarriages, preeclampsia,[67] low birth weight or fetal growth restriction[67,68] and maternal cardiac dysfunction,[69] with risks increasing with poorer hyperthyroidism control.[67,68] However, even in populations with treated hyperthyroidism, the risks of some neonatal outcomes seemed to be higher.[70,71] This indicates either inadequate hyperthyroidism management or some intrinsic effect of hyperthyroidism that increases risk for adverse neonatal health even in the presence of adequate treatment. In recent analyses from a large US cohort, diagnosed hyperthyroidism (without data on treatment) increased risk of preeclampsia, preterm birth, labor inductions, maternal and neonatal intensive care unit admissions, neonatal respiratory diseases, sepsis, cardiomyopathy, retinopathy of prematurity and neonatal thyroid diseases.[40,43] However, gestational hyperthyroidism has not been associated with adverse pregnancy outcomes.[2,35,36,72]

Treatment of Hyperthyroidism During Pregnancy

As the associations between untreated persistent hyperthyroidism and adverse pregnancy outcomes are well established, hyperthyroidism should be adequately managed before and during pregnancy.[2,5] In non-pregnant patients, the management options for Graves' disease include radioactive iodine ablation, antithyroid drug treatment and/or surgery,[3] whereas only antithyroid drugs and surgery are options in the pregnant patient.[2,5] Radioactive iodine ablation results in a long latency of 2–6 months before development of hypothyroidism as well as in an increase in TRAb titers. As such, this treatment option is not generally recommended for hyperthyroid women planning pregnancy in the near future (within 6 months of the treatment) as it is unlikely that they would have achieved a stable euthyroid state during that time.[2,3] Surgery is an option for patients hoping to conceive soon after the operation, but even then, the optimal management of hypothyroidism after total or near total thyroidectomy should be reached before conception to reduce risk of adverse pregnancy outcomes.[2,3]

In non-pregnant women with mild hyperthyroidism, antithyroid drugs are often recommended as these patients have high likelihood of remission.[3] Notably, up to 30% of patients with Graves' disease may achieve remission without treatment.[3] Generally antithyroid drugs are used in non-pregnant patients for up to 12–18 months, after which they are discontinued if TSH is normal at that time.[3] Other treatment approaches should be considered at that time if remission is not achieved, acknowledging the limitations of certain treatments if a female patient is planning to conceive in the near future.[3] Women who have achieved remission of hyperthyroidism before pregnancy with antithyroid drug therapy seem to have a low risk of hyperthyroidism relapse during pregnancy but a high relapse risk postpartum.[3] Still such women with history of treated hyperthyroidism need to be carefully monitored during pregnancy for clinical or biochemical signs of relapse as well as be tested for TRAb positivity at mid-gestation.[2]

Antithyroid drugs can also be used to control hyperthyroidism in women planning pregnancy or among those with newly discovered Graves' disease during pregnancy.[2,5] The antithyroid drug methimazole (and its prodrug carbimazole) is associated with teratogenity, including aplasia cutis and choanal or esophageal atresia.[73] However, these specific malformations are very rare on a population level. The other commonly used antithyroid drug, propylthiouracil, is not associated with teratogenity but in rare instances propylthiouracil may increase the risk of hepatotoxicity in the mother.[2,5] Current recommendations suggest using propythiouracil during preconception and in the first trimester of pregnancy to reduce teratogenity and switching to methimazole after the first trimester to reduce maternal hepatotoxicity.[2,5] However, if one antithyroid drug is not available or there are tolerance issues, either prophyltiouracil or methimazole can be used throughout pregnancy as the neonatal and maternal risks of untreated maternal hyperthyroidism outweigh the small risks of malformations or liver toxicity.[2,5]

Both antithyroid drugs have been found to be similarly effective in treating hyperthyroidism.[2,5] There are no studies to show if the prevalence of maternal symptoms or abnormal thyroid function tests increase after switching of antithyroid products during pregnancy or if the switch is related to adverse pregnancy outcomes. After switching between products, thyroid function should be promptly tested (within 2 weeks of the switch), with a subsequent follow-up every 4–6 weeks once euthyroid state is reached.[2,5] Surgery is also an option for pregnant patients where rapid control of hyperthyroidism is needed or antithyroid drugs cannot be used.[3] However, as anesthetic agents are teratogenic in the first trimester and surgery is associated with increased fetal loss in the third trimester, the late second trimester is thought to be the safest period to perform thyroidectomy in a pregnant woman.[3] As treating hyperthyroidism during pregnancy is a balance between adverse outcomes related to treatment and hyperthyroidism itself, hyperthyroidism should preferentially be already treated before conception.

Women with gestational hyperthyroidism generally do not require treatment as the condition is transient and not associated with adverse pregnancy outcomes.[2,35,36,72] Those with hyperemesis gravidarum and gestational hyperthyroidism may require hyperemesis symptom management, but generally they do not require antithyroid drug treatment.[2] Propranolol, a beta-blocker, can be used in short-term symptom management as it has some direct antithyroid activity by blocking iodide transport to the thyroid.[2] However, if women do not reach euthyroidism as pregnancy progresses or there are other symptoms, Graves' disease should be suspected and a treatment trial with antithyroid drugs may be useful.[2]

Caveats & Goals of Antithyroid Drug Treatment. All antithyroid drugs cross the placenta and may have deleterious impacts on the fetal thyroid function.[2] When treating pregnant women with antithyroid drugs, the treatment goal is to maintain fT4 values at or above the upper non-pregnant reference limit or high-normal within the pregnant reference limit (preferred approach) using the lowest possible dose of the drug.[2] Upon treatment initiation, thyroid function tests should be measured every 2–4 weeks and every 4 weeks after treatment goals are reached.[2] Maternal TSH levels may remain suppressed or low throughout pregnancy in spite of adequate antithyroid drug treatment.[2] Overtreatment with antithyroid drugs may lead to goitrogenesis and hypothyroidism in the fetus, the risk of which is thought to be lower by maintaining high-normal maternal fT4 levels.[2]

Graves' disease typically exacerbates in the first trimester of pregnancy and gradually improves afterward.[2] Consequently, up to 20–30% of all women with hyperthyroidism may discontinue antithyroid drug therapy in late pregnancy.[2] However, women with high TRAb titers continue to be at high risk of recurrence and require antithyroid drug treatment throughout pregnancy.[2]

Besides the fetal hypothyroidism risk inflicted by maternal antithyroid drug therapy, untreated maternal hyperthyroidism may lead to transient central hypothyroidism in the fetus.[2] Maternal TRAbs pass through the placenta and can lead to fetal or neonatal hyperthyroidism.[2] Women with past or present history of Graves' disease should have their TRAb titers checked in mid-pregnancy to estimate this risk as fetal hyperthyroidism is associated with increased neonatal morbidity and mortality.[2] Fetal surveillance with serial ultrasounds is required to diagnose fetal thyroid dysfunction and follow fetal growth and wellbeing if a woman has uncontrolled hyperthyroidism and/or positive TRAb during pregnancy.[2] Similarly, evaluation for thyroid dysfunction is required in neonates of women with Graves' disease or positive TRAb during pregnancy.[2]

Levothyroxine and antithyroid drugs should not be used together, except in the rare cases of fetal hyperthyroidism.[2] Administering both concurrently leads to a relative increase in maternal fT4 levels leading to increased requirements of antithyroid drugs, which in turn may lead to fetal hypothyroidism.[2]

Treatment of Hyperthyroidism During the Postpartum Period. Women with a history of Graves' disease or hyperthyroidism treated during pregnancy are at a higher risk of relapse during the postpartum period.[2] Moderate use of antithyroid drugs is safe during lactation and has not been shown to affect thyroid hormone levels or the development of the infant.[2] However, as a safety precaution, infants of mothers taking antithyroid drugs during lactation need to be followed with thyroid function tests and antithyroid drugs should be taken in divided doses immediately after feeding.[2]

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