Autoimmune Thyroid Disease and Pregnancy Treatment & Management

Hyperthyroidism

Prenatal counseling and management of Graves disease

Women with hyperthyroidism should be treated either with ablative therapy (iodine radiation or surgery) or medical therapy and become euthyroid before attempting pregnancy. For ablative therapy, TSI titers tend to increase and remain elevated for many months. A pregnancy test should be performed 48 hours before the iodine radiation ablation to avoid radiation exposure to the fetus. Conception should be delayed for 6 months postablation to allow time for the dose of T4 to be adjusted to obtain target values for pregnancy (serum TSH between 0.3 and 2.5 mIU/L).

If the patient chooses thioamide drugs (ATD therapy), propylthiouracil (PTU) should be used in the first trimester of pregnancy, because of the risk of methimazole (MMI) embryopathy; and consideration should be given to discontinuing PTU after the first trimester and switching to MMI in order to decrease the incidence of liver disease. Contraception should be used until normal thyroid function is achieved. ^{[3, 18]}

Pregnancy management

The goal of treatment is to maintain clinical euthyroidism, with the mother's FT4 level in the high-normal range. In order to prevent overtreatment and possible neonatal hypothyroidism, the lowest dose possible should be used to keep maternal free T4 and free T3 in upper limit of the normal range. ^[24]

Thioamide drugs (ie, ATDs) are the first-line treatment in pregnancy. PTU, methimazole (MMI), and carbimazole (CMI) are the ATDs available in the United States. These drugs inhibit iodination of thyroglobulin and thyroglobulin synthesis by competing with iodine for the enzyme peroxidase. PTU, MMI, and CMI are equally effective.

A controversial association exists between MMI and fetal scalp defects, aplasia cutis, and choanal and/or esophageal atresia. Some studies have reported a positive association between the two and others reported no association, which may be due to the fact that the studies showing no association were underpowered or did not assess outcomes at the optimal ages. ^[25] Additionally, PTU has recently been shown to increase the risk of malformations, usually milder than those with MMI, but a change from one to the other has not been shown to protect against birth defects. ^[26]

Because of the potential for worse malformations with MMI, PTU tends to be the first choice in this class of drugs. ^[26]  However, PTU confers a higher risk of maternal agranulocytosis and liver failure. Although in a recent Danish population-based study there were only 41 and 11 cases, respectively, per 5 million inhabitants over a 10-year period. By contrast, ATD-associated birth defects occurred in 3.4% of exposed neonates (44 cases per 5 million over 10 years). ^[27]

A 1:20 dosage ratio of MMI to PTU is recommended when transitioning from one drug to the other. ^[18]

The US Food and Drug Administration (FDA) had added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for propylthiouracil. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that propylthiouracil should be reserved for use in those who cannot tolerate other treatments such as methimazole, radioactive iodine, or surgery.

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with propylthiouracil (PTU). Of the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver transplants occurred. PTU is indicated for hyperthyroidism due to Graves disease. ^[28]

These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death). PTU is considered as a second-line drug therapy, except in patients who are allergic or intolerant to methimazole, or for women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy.

The FDA recommends the following criteria be considered for prescribing PTU. For more information, see the FDA Safety Alert.

• Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole.

• Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.

• For suspected liver injury, promptly discontinue PTU therapy and evaluate for evidence of liver injury and provide supportive care.

• PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole, and no other treatment options are available.

• Counsel patients to promptly contact their health care provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

Free T4 and TSH should be measured approximately every 2-4 weeks at initiation of therapy and every 4-6 weeks after achieving the target value.

Doses of ATDs should be maintained at the lowest dose needed to keep the mother's FT4 level in the high-normal range. Weight gain, pulse rate, FT4 results, and TSH levels should be monitored monthly.

Beta-blockers (eg, atenolol, nadolol, propranolol) are valuable adjuncts to ATDs. These drugs effectively alleviate symptoms of hypermetabolic states. With prolonged use, beta-blockers are associated with fetal morbidity. Therefore, these drugs should be used for only a short period (ie, 2 wk) while one waits for the ATDs to take effect.

Iodide decreases serum T4 and T3 levels by 30-50% in 10 days. Iodide is used in combination with ATDs and beta-blockers during the preoperative treatment of patients with hyperthyroidism. Iodide can also be used in the medical treatment of patients with thyroid storm. Fetal hypothyroidism resulting from placental passage is reported with prolonged use of iodide products; therefore, iodide use should be limited to less than 2 weeks.

Use of radioactive iodine is contraindicated in pregnancy.

The prevalence of fetal and neonatal hyperthyroidism is 1-5% in women with active or past history of Graves hyperthyroidism. Fetal and neonatal morbidity and mortality are increased if unrecognized and untreated.

A determination of serum TSI antibodies by 24–28 weeks' gestation is helpful in detecting pregnancies at risk for fetal and neonatal hyperthyroidism. Testing in the first trimester may also be helpful.

Fetal surveillance with serial ultrasounds should be performed in women who have uncontrolled hyperthyroidism and/or women with high TSI antibodies (levels greater than 3 times the upper limit of normal) or those that develop preeclampsia. Signs of potential fetal hyperthyroidism that may be detected by ultrasonography include intrauterine growth restriction, presence of fetal goiter, accelerated bone maturation, and fetal hydrops. A consultation with an experienced obstetrician or maternal–fetal medicine specialist is optimal. ^[3]

Gestational thyrotoxicosis is a transient, non-autoimmune form of the disease associated with hyperemesis gravidarum. It does not require treatment with ATDs, only supportive care, as it resolves spontaneously once human chorionic gonadotropin levels fall after the first trimester.

Postpartum hyperthyroidism

MMI in doses up to 20–30 mg/d is safe for lactating mothers and their infants. PTU at doses up to 300 mg/d is a second-line agent due to concerns about severe hepatotoxicity. ATDs should be administered following a feeding and in divided doses. Breast-feeding infants of mothers taking ATDs should be screened with thyroid function tests.

Hypothyroidism

The goal of treatment is to normalize maternal TSH levels. It should be remembered that iodine deficiency is an important cause of neonatal neurologic damage worldwide. The recommended mean intake of iodine during pregnancy and lactation is approximately 250 mcg/d.

Thyroid hormone replacement using synthetic thyroxine (T4) is the treatment for patients with hypothyroidism, which should be corrected before pregnancy occurs. A full replacement dosage of 1.6-2.0 mcg/kg/day should be started at the time of diagnosis. Preconception thyroid medication should be adjusted to achieve a TSH level of less than 2.5 mU/mL before pregnancy. Other thyroid preparations, such as T3 or desiccated thyroid, are strongly discouraged.

The goal of thyroid hormone treatment is to normalize maternal serum TSH values within the trimester-specific pregnancy reference range (first trimester, 0.1-2.5 mIU/L; second trimester, 0.2-3.0 mIU/L; third trimester, 0.3-3.0 mIU/L).

The dosage of thyroid hormone should be increased at 4-6 weeks of gestation; an increase of 25-30% may be required. This is because the increased requirement for thyroid hormone (endogenous or exogenous thyroxine) occurs as early as 4–6 weeks of pregnancy and gradually increases through 16–20 weeks of pregnancy, and thereafter plateaus until time of delivery. However, unlike healthy women, those with preexisting hypothyroidism or subclinical hypothyroidism are unable to increase thyroid hormone production. Hypothyroid women who are newly pregnant should preemptively increase their thyroid hormone dose by approximately 30% and notify their clinician promptly. This can be achieved by increasing the dosing from once daily to a total of nine doses per week (double the daily dose two days each week).

Thyroid hormone adjustments may be made as shown in the Table below.

Table. Mean Increases in Dosages of Thyroid Hormone According to Serum TSH levels (Open Table in a new window)

If hypothyroidism is diagnosed during pregnancy, the thyroid medication should be titrated rapidly to achieve TSH levels of less than 2.5 mcg. During pregnancy, the full replacement dosage of T4 is approximately 2.0-2.4 mcg/kg/d.

Results of thyroid function tests (TFTs) should be checked within 30 days after the dosage is changed. TFTs should be repeated until the results return to normal. In general, TSH should be measured every 4 weeks during the first half of pregnancy because dose adjustments are often required. TSH cam be monitored less often (at least once each trimester) in the latter half of pregnancy, as long as the dose is unchanged.

There are conflicting reports regarding whether it is beneficial to treat women who have been diagnosed with subclinical hypothyroidism during pregnancy. ^{[29, 30]}  Similarly, professional societies differ in their recommendations with the Endocrine Society favoring universal treatment, the American Thyroid Association preferring treatment only of women who are also positive for TPO antibodies, and the American College of Obstetricians and Gynecologists opting against treatment over a lack of data showing a benefit. ^{[3, 18, 21, 31]}

Patients with TPO antibodies alone or with subclinical hypothyroidism are at increased risk of preterm birth, but there is not currently enough evidence to recommend TSH and TPO antibody screening in low-risk women. ^[32] However, patients with subclinical hypothyroidism who are positive for TPO antibodies in pregnancy should be treated to normalize maternal TSH levels, but evidence is insufficient to recommend or discourage universal thyroid hormone treatment in those with subclinical hypothyroidism who are negative for thyroid antibodies. Additionally, elevated IL-6 levels in the first trimester, irrespective of thyroid autoimmunity or subclinical hypothyroidism, are a risk factor for adverse pregnancy outcomes. ^[33]

Women with subclinical hypothyroidism who are not initially treated should be monitored for progression to hypothyroidism with a serum TSH and FT4 approximately every 4 weeks until 16-20 weeks gestation and at least once between 26 and 32 weeks gestation.

Women with thyroid antibodies in pregnancy who are euthyroid should be monitored with TFTs because of their high risk of developing hypothyroidism. Serum TSH should be evaluated every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation.

After delivery, the dosage of thyroid medication should be reduced to the preconception dose. Additional TSH testing should be performed at approximately 6 weeks postpartum.

Isolated hypothyroxinemia should not be treated in pregnancy. There is theoretical concern for impaired fetal neurodevelopment in the setting of decreased availability of T4, but to date no study has demonstrated any benefit to treating women with isolated hypothyroxinemia during pregnancy. ^{[3, 21, 22]}

Iodine

All pregnant and lactating women should ingest a minimum of 250 mg iodine daily. ^{[34, 35]} To achieve a total of 250 mg iodine ingestion daily in North America, all women who are planning to be pregnant or are pregnant or breastfeeding should supplement their diet with a daily oral supplement that contains 150 mg of iodine. ^[36] Potassium iodide is the favored source because kelp and other forms of seaweed do not provide a consistent delivery of daily iodide. Strategies for ensuring adequate iodine intake during preconception, pregnancy, and lactation should vary according to regional dietary patterns and availability of iodized salt.

Sustained iodine intake from diet and dietary supplements exceeding 500–1100 mg daily should be avoided due to concerns about the potential for fetal hypothyroidism. Pharmacologic doses of iodine exposure during pregnancy should be avoided, except in preparation for thyroid surgery for Graves disease. Clinicians should carefully weigh the risks and benefits when ordering medications such as amiodarone, some local anesthetics, anti-asthmatic medications and expectorants, or diagnostic tests that will result in high iodine exposure.

Interestingly, potassium iodide has been used in Japan as an alternative to using traditional ATDs during the first trimester to better balance the risks of maternal and neonatal harm. In a retrospective cohort study, women with Graves disease, all living in an iodine-sufficient area, who were treated with potassium iodide had a lower incidence of major fetal anomalies than those treated with MMI (1.53% [4/260)] versus 4.14% [47/1134]). In the potassium iodide group, 2 (0.8%) infants had malformations consistent with MMI embryopathy compared to 18 (1.6%) in the MMI group. ^[37]

 

Hyperthyroidism

Subtotal thyroidectomy induces remission in most patients with Graves disease. Surgery should be used as the second line of treatment in pregnant women.

Surgery is reserved for patients who meet 1 of the following criteria:

• High doses of ATDs (PTU > 300 mg, MMI > 20 mg) are required.

• Clinical hyperthyroidism cannot be controlled.

• Fetal hypothyroidism occurs at the dosage needed for maternal control.

• The patient cannot tolerate ATDs.

• The patient is noncompliant.

• Malignancy is suspected.

When surgery is needed, it should be performed during the second trimester.

Hypothyroidism

No surgical care is recommended.

Consultation with perinatologists and endocrinologists is recommended.