Thyroid Disease and Pregnancy

Etiology

Hypothyroidism

The most common cause of hypothyroidism during pregnancy in iodine replenished areas is chronic autoimmune thyroiditis (Hashimoto thyroiditis).[2] Worldwide, endemic iodine (I-) deficiency is commonly associated with hypothyroidism in pregnant women.

Hyperthyroidism

Graves disease is the most common cause of overt hyperthyroidism during pregnancy.[3] Other less common causes include toxic multinodular goiter, toxic adenoma, and thyroiditis. A frequent cause of hyperthyroidism during pregnancy is transient gestational thyrotoxicosis (hCG mediated hyperthyroidism) which affects 1% to 3% of pregnancies in the first half of pregnancy and is due to elevated hCG levels.[4]

Epidemiology

During pregnancy, spontaneous hypothyroidism has a prevalence of about 2% to 3% with 0.3% to 0.5% women presenting with overt hypothyroidism and 2% to 2.5% with subclinical hypothyroidism.[5]

On the other hand, overt hyperthyroidism can affect up to 0.1% to 0.4% of the pregnancies.[6]

Pathophysiology

Normal Thyroid Physiology During Pregnancy

During pregnancy, there are increased metabolic needs of the maternal body resulting in changes in thyroid physiology. These changes in thyroid physiology reflect in altered thyroid function tests. The different changes occurring in thyroid physiology are as follow:

• An increase in serum thyroxine-binding globulin (TBG) leading to an increase in the total T4 and total T3 concentrations. Their levels peak by approximately week 16 of gestation and remain high until delivery.[7] 
• Stimulation of the thyrotropin (TSH) receptor by human chorionic gonadotropin (hCG) which increases thyroid hormone production and subsequently reduces serum TSH concentration.[4]

Therefore, compared to the non-pregnant state, women tend to have lower serum TSH concentrations during pregnancy. Studies have shown that 15% of healthy women during the first trimester of pregnancy have TSH below the non-pregnant lower limit of 0.4 mU/L.[8]

Trimester-Specific Ranges

The serum TSH concentration is the initial and most reliable measure of thyroid function during pregnancy.[9] As elaborated above, there are physiologic changes in TSH levels during pregnancy which warrants close monitoring of TSH levels. As per the latest American Thyroid Association (ATA) guidelines, serum TSH levels during pregnancy should be defined using population and trimester-specific based reference ranges. When population and trimester-specific normal ranges are not available, the ATA guidelines recommend reducing the lower limit of TSH by 0.4 mU/L and the upper limit by 0.5 mU/L. It would correspond to the TSH reference range of 0.1 to 4.0 mU/L during the first trimester with a gradual return of TSH towards the non-pregnant normal range during second and third trimesters.[1] The free T4 levels measured by immunoassays are not very reliable during pregnancy due to changes in binding proteins. Alternatively, measurement of total T4 levels or free T4 index may be more reliable.[10]

Iodine Requirement During Pregnancy

There is an increase in iodine requirement during pregnancy due to an increase in maternal thyroid hormone production as well as an increase in renal iodine clearance. Along with the above two factors, there is also a fetal iodine requirement; therefore, dietary iodine requirements are higher during pregnancy.[11] Women with sufficient iodine intake before and during pregnancy can easily adapt to the increased demand for thyroid hormone during pregnancy. However, in the areas of iodine deficiency, where iodine requirements are not optimally replenished, it frequently results in maternal iodine deficiency. It has adverse effects on the fetus including poor neurological and cognitive development. The World Health Organization (WHO) recommends 250 mcg of iodine intake daily during pregnancy and lactation.[12] The ATA guidelines recommend all pregnant women should consume approximately 250 mcg iodine daily. In the United States, women who are planning a pregnancy or are currently pregnant should supplement their diet with a daily oral supplement containing 150 mcg of iodine in the form of potassium iodide which should be started 3 months in advance of a planned pregnancy. It is important to note that excessive iodine intake should be avoided during pregnancy which is also harmful and causes fetal hypothyroidism and goiter. As per WHO, maximum permissible intake of iodine during pregnancy is 500 mcg daily.[13]

History and Physical

Hypothyroidism

History and physical examination in pregnant women with hypothyroidism are similar to those with hypothyroidism in non-pregnant adults. Many women are asymptomatic while others may have fatigue, constipation, weight gain, and cold intolerance. 

Physical examination findings may include dry skin, puffy faces, periorbital edema, delayed relaxation of deep tendon reflexes and bradycardia. 

Hyperthyroidism

Similarly, history and physical examination in pregnant women with thyrotoxicosis are identical to hyperthyroidism in non-pregnant adults. Some symptoms of hyperthyroidism may include palpitations, excessive sweating, heat intolerance, anxiety, insomnia, weight loss, and tremors.

Physical examination findings may include tachycardia, lid lag and stare, diaphoresis, and hyperreflexia. Findings specific to Graves disease include diffuse goiter, ophthalmopathy (exophthalmos), and pretibial myxedema.

Evaluation

Hypothyroidism

Hypothyroidism during pregnancy is defined as elevated TSH levels above the population and trimester-specific reference range. When it is not available, an upper reference range above 4.0 mU/L should be used. Hypothyroidism during pregnancy can present as overt hypothyroidism defined as increased trimester-specific TSH and low free T4 levels or subclinical hypothyroidism defined as increased trimester specific TSH and normal free T4 levels.

Hyperthyroidism

Overt hyperthyroidism during pregnancy is characterized by decreased TSH and increased free T4 levels. Subclinical hyperthyroidism is characterized by decreased TSH and normal free T4 levels. It is important to remember transient subclinical hyperthyroidism can be seen during the first trimester of pregnancy due to adaption in thyroid physiology as discussed above. In gestational thyrotoxicosis, there is a physiological decrease in TSH levels during the first trimester due to hCG mediated stimulation of the TSH receptor. It peaks between 7 to 11 weeks of gestation.[14] Gestational thyrotoxicosis can be differentiated from Graves disease by careful history and examination. Additionally, in Graves disease, TSH receptor antibodies are elevated on the blood test.

Treatment / Management

Hypothyroidism 

Overt hypothyroidism warrants treatment with thyroid hormone replacement with the goal to keep TSH level in trimester specific range. There is ample research demonstrating the detrimental effects of untreated overt hypothyroidism on maternal and fetal health. On the other hand, there is insufficient evidence about the treatment of subclinical hypothyroidism during pregnancy. ATA guidelines recommend subclinical hypothyroidism should be treated in females with positive TPO antibodies and TSH greater than 2.5 mU/L.[1] The thyroid function tests should be checked every 4 to 6 weeks until week 20 and at least once around the 30th week of gestation.  Most women (50% to 85%) with pre-existing hypothyroidism before pregnancy have an increased demand for thyroid hormone requirements during pregnancy which increases with progression of pregnancy by approximately 30%.[15](B2)

Hyperthyroidism 

The treatment goals for hyperthyroidism during pregnancy is to maintain mild maternal hyperthyroidism while avoiding fetal hypothyroidism.[16] To maintain mild maternal hyperthyroidism, maternal free T4/total T4 should be maintained at the upper limit of normal of the reference range using the lowest effective dose of antithyroid drugs. The treatment for hyperthyroidism during pregnancy is indicated based on etiology as well as the severity of hyperthyroidism.

Graves disease is the most common cause of thyrotoxicosis during pregnancy. The management of Graves disease complicating pregnancy is as follow:

1. Antithyroid drugs: The thionamides – methimazole (MMI) and propylthiouracil (PTU) – are most commonly used for the treatment of hyperthyroidism during pregnancy.[17] MMI is contraindicated in the first trimester of pregnancy due to potential teratogenic effects; therefore, PTU is recommended as the first line drug in the first trimester.[18] It is recommended to switch to MMI during the second trimester due to a risk of rare but severe risk of hepatotoxicity associated with PTU.[19]
2. Beta blockers: Short-term treatment with beta-blockers such as propranolol and metoprolol can be used for symptomatic control. However, long-term treatment with beta-blockers should be avoided due to the risk of intrauterine fetal growth retardation.[20]
3. Surgery: Thyroidectomy is rarely needed and only reserved for the patients who cannot tolerate thionamides due to severe side effects or when euthyroidism cannot be achieved despite using large doses of thionamides. When indicated, it should be performed during the second trimester.
(B2)

Radioactive iodine ablation is contraindicated during pregnancy.

Subclinical hyperthyroidism, as well as gestational thyrotoxicosis, do not require treatment during pregnancy and rather observation is recommended with periodic monitoring of thyroid function tests every 4 to 6 weeks.

Differential Diagnosis

The differential diagnosis for hypothyroidism as well as hyperthyroidism during pregnancy are similar to those with non-pregnant adults. Detailed discussion is beyond the scope of this review. 

Medical Oncology

Thyroid Nodules and Thyroid Cancer During Pregnancy 

The prevalence of thyroid nodules during pregnancy varies between 3% and 21%.[21][22] The evaluation and management of thyroid nodules during pregnancy are similar to those with non-pregnant patients. Thyroid ultrasound should be performed and indications to perform a fine needle aspiration (FNA) are similar as in non-pregnant patients. FNA is safe to be performed during pregnancy. All women with thyroid nodules should have a TSH level measured to rule out toxic adenoma.

The prevalence of thyroid cancer varies widely due to differences in study design and patient population. The prognosis of differentiated thyroid cancer (DTC) is not largely influenced by pregnancy.[23] Given the slow growth of DTC, definitive management (thyroidectomy) can usually be delayed up until after delivery. The biopsy proven thyroid cancer nodules should be monitored with thyroid ultrasound every trimester. In rare circumstances, such as rapidly growing thyroid nodules or in the presence of metastases, surgery is indicated during pregnancy. In such cases, the second trimester is the safest period for performing the surgery.[1][24]

Complications

Hypothyroidism

Untreated hypothyroidism during pregnancy may result in adverse maternal and fetal outcomes including preterm labor, preeclampsia, preterm delivery, gestational hypertension, postpartum hemorrhage, low birth weight, neuropsychological and cognitive impairment in the fetus, and increased perinatal morbidity and mortality.[25]

Hyperthyroidism

Similarly, untreated or inadequately treated hyperthyroidism during pregnancy is associated with an increased risk of preterm labor, spontaneous abortion, intrauterine growth restriction, pre-eclampsia, low birth weight, stillbirth, and fetal malformations.[26]