A 27-year-old woman presents for evaluation of abnormal thyroid function tests; she is currently 10 weeks pregnant. She has previously been healthy and is taking no medications except a prenatal multivitamin. A serum thyroid-stimulating hormone (TSH) was obtained and was <0.01 mIU/l. Follow-up peripheral thyroid hormone tests were: total thyroxine (T4) 18 μg/dl (nonpregnancy reference range 4.5–10.5 μg/dl), free thyroxine index (FT4I) 6.2 (nonpregnancy reference range 1.0–4.0), and total triiodothyronine (T3) 390 ng/dl (nonpregnancy reference range 60–181 ng/dl). She complains of nausea with frequent emesis that started about 3 weeks ago. She also complains of fatigue, anxiety, occasional palpitations, and heat intolerance. She has lost 2 lbs. over the past 3 weeks. Her family history is significant for hypothyroidism in a maternal grandmother. She has no lid lag, exophthalmos, or stare. Her thyroid is easily palpable, without nodules or tenderness.

A thyroid hormone receptor antibody (TRAb) is 310 % of controls (normal <140 %). She is diagnosed with Graves’ disease and propylthiouracil (PTU) 50 mg three times daily is started. She is also started on propranolol. Four weeks later (at 14 weeks gestation), she reports that symptoms are much improved. Her thyroid function tests are as follows: serum TSH <0.01 mIU/l, total T3 265 ng/dl, total T4 16 μg/dl, and FT4I 4.3. She is changed from PTU to methimazole (MMI) 15 mg daily, and the propranolol is stopped. Thyroid function is measured again at 4-week intervals and remains normal for pregnancy. The MMI dose is decreased to 10 mg daily at 22 weeks gestation and to 5 mg daily at 28 weeks; she remains on this dose until delivery. A repeat serum TRAb value is obtained at 22 weeks gestation and is 150 % of controls. An ultrasound performed at 28 weeks gestation demonstrates a fetal heart rate of 140 bpm and a no sign of fetal goiter or growth retardation. Six weeks after uneventful delivery of a full-term infant, thyroid function is again measured and remains normal on MMI; the patient is breastfeeding.

Thyrotoxicosis is diagnosed by the presence of a suppressed serum TSH concentration. Peripheral thyroid hormones (free T4 and/or total T3) are elevated in overt hyperthyroidism, but remain within the normal range in subclinical hyperthyroidism. Importantly, serum thyroid hormone levels change over the course of normal gestation and nonpregnant reference ranges do not apply in pregnancy [1, 2]. TSH is the most sensitive indicator of thyroid status. Human chorionic gonadotropin (hCG) is a weak thyroid stimulator, binding to the TSH receptor. During the first trimester, when hCG levels are highest, serum TSH concentrations are often slightly below or at the low end of the non-pregnant normal range. High estrogen levels in pregnant women induce increased concentrations of circulating thyroxine-binding globulin (TBG). Therefore, total T3 and T4 levels are increased throughout pregnancy. Where trimester-specific assay-specific normal ranges are not available, the upper limit for total T3 and T4 levels in pregnancy can be estimated as 1.5 times the upper limit of the assay reference range for nonpregnant individuals [3]. Free T4 levels typically are highest in the first trimester and decline later in gestation [4].

Thyrotoxicosis in pregnancy is most frequently caused by gestational thyrotoxicosis (transient hyperthyroidism caused by elevated serum hCG levels) or Graves’ disease. Toxic nodular goiter is a less common cause. Symptoms such as fatigue, heat intolerance, and tachycardia are common to both pregnancy and all forms of thyrotoxicosis. Definitive diagnosis can also be more difficult in pregnancy because radioactive iodine thyroid scans are contraindicated. Several clinical clues may help to elucidate the diagnosis. A history of hyperthyroid symptoms that began prior to the pregnancy makes gestational thyrotoxicosis less likely. The presence of a diffuse goiter favors Graves’ disease. Ophthalmopathy or pretibial myxedema may be present only in Graves’ disease. Gestational thyrotoxicosis is more common with multiple gestation, where peak serum hCG concentrations are far higher than in single pregnancies. Gestational thyrotoxicosis is also more common in women with morning sickness, particularly in those with the most severe form, hyperemesis gravidarum (defined as persistent vomiting, ketonuria, and at least 5 % weight loss) [5]. Serum thyroid hormone receptor antibody (TRAb) is frequently positive in Graves’ disease, and may be helpful in determining the etiology of thyrotoxicosis.

Gestational thyrotoxicosis does not require antithyroid drug treatment and resolves spontaneously as hCG levels fall after the 11th week of gestation [1, 2, 6]. Care is supportive, with antiemetics and management of dehydration. Subclinical hyperthyroidism, regardless of cause, is not associated with adverse maternal or fetal outcomes [7], and therefore requires monitoring, but not treatment.

Women with untreated overt Graves’ hyperthyroidism during pregnancy are at increased risk for having low birth weight infants, stillbirths, preterm delivery, severe preecclampsia, congestive heart failure, placental abruption, and possibly for having infants with congenital malformations [1]. The antithyroid drugs PTU and MMI are the mainstay of Graves’ therapy. Small amounts of both PTU and MMI cross the placenta and may decrease fetal thyroid function. Therefore, treatment with relatively low doses of anti-thyroid drugs to keep the free T4 of pregnant women in the high–normal to slightly thyrotoxic range is recommended [1, 2]. MMI has been associated with congenital anomalies including cutis aplasia and esophageal and choanal atresia in several case reports [8]. A recent registry study demonstrated that both MMI and PTU were associated with an increased prevalence of birth defects, although birth defects were less frequent with PTU [9]. For this reason, PTU may be preferable to MMI for the treatment of hyperthyroidism in the first trimester, during the period of organogenesis [10]. However, because PTU has been associated with a risk for fulminant hepatic failure [11], changing from PTU to MMI after the first trimester is currently recommended [1, 2]. Frequent monitoring of thyroid function tests (approximately every 4 weeks) is required throughout pregnancy in women taking anti-thyroid drugs. In 20–30 % of women, Graves’ disease remits spontaneously in the last trimester of pregnancy, and antithyroid drugs can be discontinued [12]. However, they often need to be restarted postpartum.