Thyroid dysfunction is a commonly encountered endocrine disorder during pregnancy. Overt thyroid dysfunction occurs in almost 1% of all pregnant women [1,2]. The management of thyroid disease during pregnancy has been reviewed in the guidelines of several societies including the American Thyroid Association (ATA) and the Endocrine Society and the European Thyroid Association (ETA) [3,4,5]. It is well documented that maternal overt thyroid dysfunction is associated with an increased risk in adverse maternal and fetal outcomes. However, there is conflicting evidence as to whether subclinical hypothyroidism (SCH) is associated with adverse pregnancy outcomes, and whether universal thyroid screening during pregnancy is efficacious. Therefore, this review summarizes the management of thyroid disease during pregnancy with reference to several published guidelines and recent data.

Various hormonal changes and increased metabolic demands occur during pregnancy and profoundly affect thyroid function. It is important to understand both the expected changes in thyroid function test results during a normal pregnancy and the potential effects of pregnancy on preexisting thyroid diseases [6]. The major expected changes during normal pregnancy are an increase in the serum thyroxine-binding globulin (TBG) concentration and the stimulation of the thyrotropin (TSH) receptor by human chorionic gonadotropin (hCG) [7]. The serum TBG concentration rises almost two-fold during the first 20 weeks of gestation, and as a result, both serum total thyroxine (T4) and triiodothyronine concentrations increase [8]. The serum hCG concentration increases after fertilization and peaks at 10 to 12 weeks. During this peak, the thyrotropic activity of hCG reduces the concentration of serum TSH [9]. Later in pregnancy, the serum TSH concentration steadily returns to the normal range and the serum free T4 concentration declines [10].

Maternal thyroid hormones play an important role in fetal development. Because the fetal thyroid only produces thyroid hormones after 16 weeks of gestation, fetal development depends on the state of the maternal thyroid for the first half of pregnancy [11]. Therefore, maternal thyroid dysfunction can result in adverse outcomes for the fetus as well as the mother.

Due to the lack of typical symptoms of thyroid dysfunction during pregnancy, thyroid dysfunction must be diagnosed by a thyroid function test. The serum TSH concentration is the initial and most reliable measure of thyroid function during pregnancy [12]. Due to the physiologic changes in TSH levels during pregnancy, the ATA guidelines recommend using trimester-specific reference ranges for TSH [3]. If these reference ranges are not available in the laboratory, the following reference ranges can be used: first trimester, 0.1 to 2.5 mIU/L; second trimester, 0.2 to 3.0 mIU/L; third trimester, 0.3 to 3.0 mIU/L. Serum TSH concentration may also be affected by many other factors including analytical method, thyroid autoantibody status, ethnicity, and iodine nutrition. Since the reference range for the first trimester in the ATA guidelines was derived from studies during weeks 9 to 12 of gestation, this cutoff has been too low for pregnant women visiting the clinic before 8 weeks of gestation [13]. Also, different reference ranges for TSH in the first trimester have been reported for different populations [14]. Therefore, the correct interpretation of thyroid function tests requires knowledge of a woman's gestational week and the appropriate population-based reference interval [15,16].

In iodine-sufficient areas, the most common cause of hypothyroidism during pregnancy is chronic autoimmune thyroiditis. The diagnosis of hypothyroidism is based on an elevated serum TSH concentration. When serum TSH is elevated, measurement of the serum free T4 concentration is required to classify the patient's status as either SCH or overt hypothyroidism (OH) [3]. OH is defined as an elevated trimester-specific TSH concentration with a reduced free T4 concentration, or an elevated TSH concentration (>10 mIU/L) irrespective of the free T4 level. The prevalence of OH during pregnancy has been estimated to be 0.3% to 0.5% [2]. Untreated OH is associated with an increased risk of adverse pregnancy complications, including premature birth, low birth weight, and miscarriage [17,18]. Haddow et al. [19] indicated that untreated OH during pregnancy may have detrimental effects on the neuropsychological development of the unborn child. SCH is defined as an elevated trimester-specific serum TSH concentration with a normal free T4 level. Early studies reported the prevalence of SCH to be 2% to 2.5% in pregnant women [20]. However, recent studies utilizing the ATA criteria for SCH (TSH >2.5 mIU/L) have reported that the prevalence may be as high as 27.8% [13,21,22].

In many observational studies, SCH in pregnancy has been found to be associated with adverse outcomes for both the mother and the offspring, including gestational diabetes, gestational hypertension, placental abnormalities, miscarriage, preterm labor, and low birth weight [20,23]. However, other studies have not found any association between SCH and pregnancy complications [24,25]. At present, the harmful effects of maternal SCH on fetal neuropsychological development are less clear. Some studies have found an association of SCH in early pregnancy with poor intellectual and motor development in the offspring [26,27]. However, other studies have not found any association between SCH in mothers and the neuropsychological development of their children [28,29,30].

Because of the clear association between OH and adverse outcomes for both the mother and the offspring, OH in pregnancy should be treated. However, the treatment of SCH is not universally recommended, since there are limited data demonstrating the beneficial effects of levothyroxine (LT4) treatment on obstetric outcomes. One randomized control study demonstrated that treatment of SCH pregnant women with LT4 reduced the occurrence of adverse events in both the mother and the fetus [31]. Subgroup analysis of the Controlled Antenatal Thyroid Screening (CATS) study revealed that maternal abnormal thyroid function was associated with certain adverse obstetric outcomes, while LT4 treatment may improve these outcomes [32]. In a randomized controlled trial to assess the effects of LT4 treatment on cognitive function, LT4 treatment for maternal SCH did not improve the cognitive function of children at 3 years of age [33]. In addition, in another randomized, double-blinded, placebo-controlled trial, treatment for maternal SCH did not improve cognitive outcomes in offspring at 5 years of age [34].

While ATA guidelines recommend the treatment of pregnant women who have SCH and positive thyroid peroxidase (TPO) antibodies, the guidelines of the Endocrine Society and the ETA recommend LT4 treatment for all pregnant women with SCH, irrespective of their TPO antibodies [3,4,5]. The goal of hypothyroidism treatment is to maintain the serum TSH levels within the trimester-specific reference range. Thyroid function tests should be conducted every 4 to 6 weeks during the first trimester and once during the second and third trimesters, and the dose of LT4 should be adjusted [3].

Women being treated for hypothyroidism before pregnancy need to increase their LT4 dose during pregnancy [35]. The dose requirement may increase by 30% to 50% during pregnancy and as early as 4 to 6 weeks of gestation, and may gradually increase through 16 to 20 weeks of gestation [3,36].

Overt thyrotoxicosis occurs in 0.2% to 0.4% of all pregnancies [1,18,37]. The diagnosis of overt hyperthyroidism during pregnancy should be based on a reduced serum TSH value and an elevated free T4 level that exceeds the normal range for pregnancy [3]. The most common cause of autoimmune hyperthyroidism in pregnancy is Graves' disease. However, in the first half of gestation, gestational transient thyrotoxicosis may occur in 2% to 3% of all pregnancies [7,11,38]. It is important to differentiate Graves' hyperthyroidism from gestational transient thyrotoxicosis, since the two diseases have distinct clinical courses and are managed differently [39]. The findings of a history of thyroid disease, goiter, ophthalmopathy, and TSH receptor antibody (TRAb) positivity favor the diagnosis of Graves' hyperthyroidism [40]. Gestational transient thyrotoxicosis does not require antithyroid treatment, since the serum T4 level returns to normal by 14 to 18 weeks gestation [1].

Subclinical hyperthyroidism is defined as a reduced serum TSH concentration, with free T4 levels within the normal reference range. It has not been associated with adverse pregnancy outcomes; therefore, the treatment of pregnant women with subclinical hyperthyroidism is not required [41].

Overt hyperthyroidism can adversely affect the mother and child, depending on the severity of the disease. Inadequately treated maternal hyperthyroidism has been associated with a high risk of preeclampsia, heart failure, preterm delivery, low birth weight, and fetal loss [42,43]. Propylthiouracil or methimazole can be used to treat pregnant women with overt hyperthyroidism to minimize the risk of adverse outcomes. However, the use of an antithyroid drug in early pregnancy is associated with birth defects in 3.4% of exposed children [44]. Propylthiouracil has been the preferred treatment for overt hyperthyroidism in pregnancy because it crosses the placenta less readily than methimazole, and the birth defects associated with propylthiouracil (mainly aplasia cutis, choanal or esophageal atresia, and dysmorphic facies) seem less severe than those associated with methimazole [45,46]. However, the U.S. Food and Drug Administration warned about the risk of hepatotoxicity associated with the use of propylthiouracil [47]. Correspondingly, most professional societies have recommended propylthiouracil therapy during the first trimester followed by a switch to methimazole in the second and third trimesters [3,4,48].

The goal of overt hyperthyroidism treatment is to maintain the serum free T4 concentration in the upper normal range. Serum free T4 and TSH levels should be assessed every 2 to 4 weeks with dose adjustment. Once euthyroidism is achieved, patients should be monitored every 4 to 8 weeks [3]. The natural course of Graves' hyperthyroidism gradually improves in late pregnancy, so antithyroid drug dose adjustment is needed in the second and third trimesters [49]. β-Blocker treatment may be used to control hypermetabolic symptoms in severe hyperthyroidism. However, this agent should be discontinued within 2 weeks, since long-term use of β-blockers has been associated with intrauterine growth restriction, fetal bradycardia, and neonatal hypoglycemia [50].

The prevalence of fetal hyperthyroidism is 1% to 5% in pregnant women with Graves' hyperthyroidism [51]. Persistently high levels of maternal serum TRAb have been associated with fetal hyperthyroidism [52]. Therefore, it is recommended that the TRAb test be performed by 24 to 28 weeks of gestation to predict the risk of fetal thyroid dysfunction [53]. Fetal thyroid assessment by ultrasound is recommended in women with uncontrolled hyperthyroidism or high TRAb titers. Fetal tachycardia (>170 beats per minute), growth restriction, goiter, accelerated bone maturation, heart failure, and hydrops are suspicious ultrasound findings of fetal hyperthyroidism [51,52].

Although the adverse maternal and fetal effects of untreated overt thyroid dysfunction have been well described, the association between untreated SCH and adverse pregnancy outcomes are less well defined. Therefore, performing thyroid function screening for all asymptomatic pregnant women is controversial. Negro et al. [31] demonstrated that the treatment of thyroid dysfunction detected by universal screening prevented adverse outcomes in pregnant women. However, in the CATS study, antenatal universal thyroid screening and treatment of maternal thyroid dysfunction did not improve Intelligence Quotient (IQ) scores in offspring [36]. Large prospective randomized controlled trials for the universal screening and treatment of pregnant women with SCH are underway, but the results of these trials have not yet been published [54,55].

Because there is insufficient evidence favoring universal thyroid screening in pregnant women, most professional societies recommend a case-finding approach targeting thyroid function testing in high-risk groups [3,4,5,48]. Targeted screening includes women who have a personal history, symptom, or sign of a thyroid disorder, a positive family history, and thyroid antibody positivity [3,4]. However, some recent studies have estimated that targeted thyroid function testing would miss about 30% to 55% of pregnant women with hypothyroidism [31,56,57]. Additionally, universal thyroid screening could detect 200 to 300 women with undiagnosed OH per 100,000 pregnancies [58]. Therefore, some endocrinologists have argued for the universal screening of pregnant women for overt thyroid disease based on the results of the early detection and treatment of OH during pregnancy [57,59].

Maternal overt thyroid dysfunction is associated with an increased risk of adverse outcomes. To date, there has been conflicting evidence regarding the association of SCH with adverse pregnancy outcomes and the efficacy of universal thyroid screening during pregnancy. Large prospective randomized controlled trials are needed to resolve these controversies. Results from these studies have the potential to greatly change the management of pregnant women with thyroid dysfunction.