Physiological changes to thyroid function in pregnancy

Maternal thyroid function changes throughout gestation. When evaluating measurements of thyroid function in pregnant women, it is important to keep in mind that nonpregnancy laboratory reference ranges do not apply. In the first trimester, serum human chorionic gonadotropin (hCG) acts as a stimulator of thyroidal thyrotropin receptors. Therefore, serum thyroid-stimulating hormone (TSH) levels are typically low when hCG levels are high, and they start to increase after 10–12 weeks of gestation, when the hCG levels fall . Conversely, serum free T4 levels are highest when hCG levels are elevated and tend to fall later in pregnancy. High serum estrogen levels in pregnant women increase levels of thyroxine-binding globulin (TBG) and thus increase circulating total (not free) triiodothyronine (T3) and thyroxine (T4) levels, starting early in gestation .

The use of trimester-specific, assay-specific normal ranges for thyroid function is recommended. Where such ranges are not available, the following ranges for TSH may be used: 0.1–2.5 mIU/L in the first trimester, 0.2–3.0 mIU/L in the second trimester, and 0.3–3.0 mIU/L in the third trimester . High serum TBG levels interfere with immunoassays for free T4 levels, making these assays unreliable in pregnant women . The free thyroxine index, calculated from measurements of total T4 and T3 resin binding, may be more accurate in pregnancy than free T4 immunoassays , although this remains controversial. In general, TSH is the most sensitive indicator of thyroid status in pregnant women.

Hyperthyroidism in pregnancy

Overt hyperthyroidism, which occurs in 0.1–0.4% of pregnant women, is defined as a serum TSH level below the trimester-specific reference range with elevated levels of T3 and/or free T4. Subclinical hyperthyroidism is defined as a serum TSH level below the trimester-specific reference range with normal peripheral thyroid hormone levels. Subclinical maternal hyperthyroidism has not been associated with adverse maternal or fetal outcomes , and treatment for this condition is not recommended.

Hyperthyroidism in pregnancy

Overt hyperthyroidism, which occurs in 0.1–0.4% of pregnant women, is defined as a serum TSH level below the trimester-specific reference range with elevated levels of T3 and/or free T4. Subclinical hyperthyroidism is defined as a serum TSH level below the trimester-specific reference range with normal peripheral thyroid hormone levels. Subclinical maternal hyperthyroidism has not been associated with adverse maternal or fetal outcomes , and treatment for this condition is not recommended.

Gestational thyrotoxicosis

Gestational thyrotoxicosis is the most frequent cause of hyperthyroidism in the first trimester. It is a transient form of thyrotoxicosis due to elevated serum hCG levels . It often occurs in women with hyperemesis gravidarum (defined as severe nausea and vomiting with dehydration, the loss of 5% of body weight, and ketonuria). HCG concentrations correlate with the severity of nausea, and gestational thyrotoxicosis is unusual in women without clinically significant nausea and vomiting . Gestational thyrotoxicosis is also frequent in twin or other multiple pregnancies, where serum hCG levels are especially elevated. Gestational thyrotoxicosis does not require antithyroid drug treatment, and it resolves spontaneously as hCG levels fall after week 10–12 of gestation . Care is supportive, with hydration and antiemetics.

Graves’ disease

Graves’ disease is the most common cause of autoimmune hyperthyroidism in pregnancy; it may cause overt or subclinical hyperthyroidism. Symptoms such as fatigue, heat intolerance, and tachycardia are common to both pregnancy and to all forms of hyperthyroidism. Graves’ disease can be distinguished from gestational thyrotoxicosis by the presence of a diffuse goiter, a history of hyperthyroid symptoms prior to pregnancy, or the presence of ophthalmopathy. Measurement of serum thyroperoxidase (TPO) antibodies and/or thyroid hormone receptor antibodies may help to confirm the diagnosis of Graves’ disease.

Uncontrolled overt Graves’ hyperthyroidism is associated with increased risks of miscarriage, stillbirth, preterm delivery, preeclampsia, low birth weight, intrauterine growth restriction, thyroid storm, and maternal congestive heart failure . The antithyroid drugs propylthiouracil (PTU) and methimazole (MMI) block thyroid hormone synthesis, and they are the mainstay of Graves’ disease therapy. In the UK and other regions, carbimazole (CBZ), a metabolite of MMI, is also available. Small amounts of PTU, CBZ, and MMI cross the placenta and may decrease fetal thyroid function . Methimazole and carbimazole are associated with cutis aplasia and with a rare embryopathy consisting of choanal or esophageal atresia and dysmorphic facies . First-trimester use of PTU has also been associated with birth defects such as urinary tract and face and neck malformations . In addition, PTU has been associated with fulminant hepatotoxicity, including in pregnant women and their fetuses . Although current guidelines recommend changing women from MMI/CBZ to PTU as soon as pregnancy is confirmed, and then changing back to MMI/CBZ after the first trimester , this approach has not been studied, and some consider that the balance of risks between the two classes of antithyroid drug does not warrant the potential loss of control of hyperthyroidism in the first trimester. Treatment with the lowest possible doses of antithyroid drugs should be employed to keep the free T4 of pregnant women in the high-normal to slightly thyrotoxic range .

In women initiated on antithyroid drugs during pregnancy, serum TSH and free T4 should be assessed every 2–4 weeks until euthyroidism is achieved, and every 4–8 weeks thereafter. In up to a third of women, Graves’ disease remits spontaneously in the last trimester of pregnancy, and antithyroid drugs can frequently be discontinued . Short-term use of propranolol will improve thyrotoxic symptoms until hyperthyroidism is controlled . In women who are unable to tolerate antithyroid drugs, thyroidectomy may be required for control of Graves’ hyperthyroidism. Thyroidectomy is safest in the second trimester.

Fetal and neonatal thyroid dysfunction can occur in Graves’ disease due to transplacental passage of antithyroid drugs and/or thyroid receptor antibodies . Thyroid receptor antibodies often persist in women who have previously undergone radioactive iodine treatment or thyroidectomy. Because passage of thyroid receptor antibodies increases at around 26 weeks of gestation, it is recommended that maternal serum thyroid receptor antibody levels should be measured by 20–24 weeks of gestation in all women with a history of Graves’ disease . Thyroid receptor antibody titers exceeding 300% of the upper normal limit suggest that the fetus may be at a risk of hyperthyroidism. Ultrasound may be used to assess for signs of fetal hyperthyroidism (fetal tachycardia, accelerated bone maturation, fetal goiter, intrauterine growth restriction, and signs of congestive heart failure) and fetal hypothyroidism (goiter and retarded bone maturation) .

Hypothyroidism in pregnancy

Hypothyroidism occurs in 2–3% of pregnant women, and it is most frequently caused by Hashimoto’s thyroiditis . Hypothyroidism is subclinical (normal trimester-specific free T4 with elevated serum TSH) in the majority of hypothyroid pregnant women, with about 0.5% of pregnant women having overt hypothyroidism (elevated serum TSH and low serum free T4) . Isolated maternal hypothyroxinemia may also occur; this is defined as normal trimester-specific TSH levels with low serum free T4 concentrations.

Overt hypothyroidism is associated with adverse obstetric and fetal outcomes including miscarriage, stillbirth, gestational hypertension, preterm delivery, low birth weight, and decreased child intelligence . All overtly hypothyroid pregnant women should be treated with levothyroxine, with the goal of normalizing trimester-specific serum TSH values. The effects of subclinical hypothyroidism on pregnancy outcomes are less clear. Several observational studies have demonstrated associations between maternal subclinical hypothyroidism and adverse outcomes including miscarriage, gestational diabetes, preterm delivery, placental abruption, and decreased child intelligence quotient (IQ) . However, interventional studies demonstrating improvement in maternal or fetal outcomes with treatment for subclinical hypothyroidism are largely lacking. A single study demonstrated improved outcomes with levothyroxine treatment of TPO-antibody-positive women with first-trimester serum TSH values >2.5 mIU/L . However, a large multicenter randomized clinical trial that examined the effects of levothyroxine therapy for pregnant women with subclinical hypothyroidism (defined as TSH >97.5th centile and/or free T4 <2.5th centile) failed to demonstrate an effect on cognitive function in offspring at the age of 3 .

Because of the limited interventional data demonstrating treatment benefit, recommendations regarding the treatment of subclinical hypothyroidism in pregnancy are variable. The Endocrine Society recommends levothyroxine treatment for all subclinically hypothyroid women . The American College of Obstetrics and Gynecology recommends against treatment for pregnant women with subclinical hypothyroidism due to a lack of data for benefit . The American Thyroid Association advocates levothyroxine treatment in TPO-antibody-positive women with serum TSH >2.5 mIU/L and for all women with TSH >10.0 mIU/L, but it notes that insufficient evidence exists to recommend either for or against treating women who test negative for thyroid antibodies and who have TSH levels 2.5–10.0 mIU/L . Isolated maternal hypothyroxinemia should not be treated, as there is no evidence for improved maternal or fetal outcomes with levothyroxine treatment .

Most women treated with levothyroxine prior to pregnancy will need an increase in their thyroid hormone dose in order to maintain euthyroidism during pregnancy . Most authorities recommend increasing the dose of levothyroxine by 25–30% as soon as pregnancy is diagnosed, or by instructing women to increase their levothyroxine tablet intake from seven to nine pills per week as soon as they learn that they are pregnant . In women treated with levothyroxine, serum TSH should be measured every 4 weeks during the first 16 weeks of pregnancy and at least once during the second half of pregnancy . Immediately after delivery, the prepregnancy levothyroxine dose can be resumed, with serum TSH testing performed approximately 6 weeks following delivery.

Whether or not all pregnant women should be screened in order to detect and treat cases of maternal hypothyroidism has been extremely controversial, largely because of the uncertainty about whether treatment of subclinical hypothyroidism improves outcomes. Currently, the American College of Obstetrics and Gynecology recommends against screening, the American Thyroid Association advocates case finding in high-risk patients (including those with positive TPO antibodies, a history of autoimmune disorders, age >30 years, morbid obesity, a history of miscarriage or premature delivery, or a personal or family history of thyroid dysfunction) rather than screening, and the Endocrine Society guidelines task force was unable to reach consensus regarding universal screening versus a case-finding approach . Studies have suggested that a case-finding approach may fail to identify up to 80% of pregnant women with hypothyroidism . Not surprisingly, in light of the conflicting guidelines, current practices regarding testing for thyroid function in asymptomatic pregnant women are highly variable in terms of region.

Thyroid autoimmunity in pregnancy

Detectable TPO and/or thyroglobulin antibodies are present in 10–20% of women of childbearing age . Based on a recent meta-analysis, the risk of miscarriage is increased threefold in euthyroid women with detectable antithyroid antibodies . In the same study, thyroid autoimmunity was also associated with a twofold increased risk of preterm delivery. The reasons for this increased risk are not well understood. One possibility is that women with antithyroid antibodies may have subtly decreased thyroid function, which is responsible for the adverse pregnancy effects . Antithyroid antibodies may be a marker for abnormal T cell function, and the adverse effects on pregnancy outcomes may be mediated by inflammation and altered cytokines . TSH-receptor-blocking antibodies are present in some women with thyroid autoimmunity, and these could potentially bind to and inhibit hCG receptor on the corpus luteum . Finally, antithyroid antibodies might simply be markers for other, non-organ-specific antibodies, which mediate adverse pregnancy effects.

In a prospective clinical trial, TPO-antibody-positive euthyroid pregnant women were randomized to treatment with levothyroxine versus no treatment starting in early gestation . This study reported a substantial reduction in the risk of preterm delivery and miscarriage in the levothyroxine-treated women. However, although similar studies are currently ongoing in the UK and in the Netherlands , to date, this study has not been replicated, and treatment of euthyroid TPO-antibody-positive pregnant women is not currently recommended .