Hypothyroidism and Pregnancy
1. What every clinician should know
Overt hypothyroidism complicates between 1/1,000 and 3/1,000 pregnancies. Women with overt hypothyroidism are at an increased risk for pregnancy complications such as early pregnancy failure, preeclampsia, placental abruption, low birth weight and stillbirth. Treatment of women with overt hypothyroidism has been associated with improved pregnancy outcomes.
The most common cause of primary hypothyroidism in pregnancy is chronic autoimmune thyroiditis Hashimoto’s thyroiditis). This is painless inflammation with progressive enlargement of the thyroid gland characterized by diffuse lymphocytic infiltration, fibrosis, parenchymal atrophy and eosinophilic change. Other important causes of primary hypothyroidism include endemic iodine deficiency and a history of either ablative radioiodine therapy or thyroidectomy.
Secondary hypothyroidism is pituitary in origin. For example, Sheehan’s syndrome from a history of obstetrical hemorrhage is characterized by pituitary ischemia and necrosis with subsequent deficiencies in some or all pituitary hormones. Other etiologies of secondary hypothyroidism include lymphocytic hypophysitis and a history of a hypophysectomy.
Tertiary or hypothalamic hypothyroidism is very rare. Central hypothyroidism refers to inadequate stimulation of the thyroid gland because of a defect at the level of the pituitary or hypothalamus.
2. Diagnosis and differential diagnosis
The presence or absence of a pathologically enlarged thyroid gland (i.e. goiter) depends on the etiology of hypothyroidism. Women in areas of endemic iodine deficiency or those with Hashimoto’s thyroiditis are much more likely to have a goiter. It is characterized by vague, nonspecific signs or symptoms that are often insidious in onset. Initial symptoms include fatigue, constipation, cold intolerance and muscle cramps. These may progress to insomnia, weight gain, carpal tunnel syndrome, hair loss, voice changes and intellectual slowness.
Other signs of hypothyroidism include periorbital edema, dry skin and prolonged relaxation phase of deep tendon reflexes. The diagnosis of clinical hypothyroidism during pregnancy is particularly difficult since many of the signs or symptoms listed above are also common to pregnancy. Thyroid testing should be performed on symptomatic women or those with a personal history of thyroid disease.
The mainstay for the diagnosis of thyroid disease is the measurement of serum TSH. Serum TSH is more sensitive than free-T4 for detecting hypo- and hyperthyroidism. If the TSH is abnormal, then evaluation of free- T4 is recommended. A disadvantage of this TSH-first testing strategy is that unusual thyroid conditions characterized by discordant TSH and free-T4 results may go undetected. The diagnosis of overt hypothyroidism is generally established by an elevated serum TSH and a low serum free-T4.
The reference range for serum TSH concentrations in non-pregnant individuals is 0.45-4.5 mU/L. However, recent data indicates that more than 95% of normal individuals have a TSH level below 2.5 mU/L and that those with a TSH between 2.5 and 4.5 mU/L have an increased risk of progression to overt disease. This has led some to recommend a decrease in the upper limit of the TSH reference range to 2.5 mIU/L, while others suggest that this change would only increase the diagnosis of subclinical hypothyroidism without clear evidence for a benefit from treatment.
During early pregnancy there is a fall in serum TSH and a modest increase in free-thyroxine because of the structurally related thyroid-stimulating activity of human chorionic gonadotropin. These physiologic changes confound the diagnosis of hypothyroidism during pregnancy and highlight the need for gestational age-specific TSH thresholds (see Figure 1). Such thresholds have been reported and are based on a large population-based study of pregnant women.
For example, the upper limit of the statistically defined normal range for TSH (97.5th percentile) in the first half of pregnancy has been reported to be 3.0 mU/L. Moreover, if population-specific medians for TSH are determined for each trimester at a particular laboratory, these data indicate the upper limit of TSH during the first trimester should be 4.0 multiples of the median (MoM) and 2.5 MoM for the second and third trimester in singleton gestations.
The impact of changes in free-T4 levels during normal pregnancy have been the subject of much controversy, particularly with the advent of automated free hormone immunoassays. The diagnostic accuracy of these free-T4 tests are dependent on protein binding, especially given the physiological changes in thyroid binding globulin (TBG) and other proteins during pregnancy.
Though there is a significant decrease in free-T4 in late gestation when compared to nonpregnant women or those in the first trimester, overall free-T4 concentrations remain within the reference range (0.7-1.8 ng/dL) throughout pregnancy. Therefore, use of nonpregnant free-T4 thresholds for diagnosis of hypothyroidism is recommended.
It may also be helpful to confirm the presence of antimicrosomal antibodies in pregnant women with hypothyroidism. Specifically, the presence of antithyroid antibodies may identify a population of women at a particular risk for pregnancy complications, postpartum thyroiditis and progression to symptomatic disease. One recent study revealed that 50% of women identified with TPO antibodies at 16 weeks gestation developed postpartum thyroid dysfunction and one in four of these women went on to develop permanent overt hypothyroidism within the year.
Subclinical hypothyroidism is defined by an elevated serum TSH level but abnormal serum thyroxine concentration. Reports suggesting increased fetal wastage or subsequent neurodevelopmental complications in the offspring of women with mild hypothyroidism have prompted recommendations that levothyroxine be prescribed to restore the TSH level to the reference range in these women. However, there are no published intervention trials specifically assessing the efficacy of such treatment to improve neuropsychological performance in offspring of women with subclinical hypothyroidism (i.e. elevated TSH and normal free-T4).
Recently, results from the International Controlled Antenatal Thyroid Screening (CATS) Study revealed that treatment of women with either subclinical hyporthyroidism or isolated hypothyroxinemia did not improve intellectual function of offspring at age 3. Routine screening and treatment of subclinical thyroid disease during pregnancy is not recommended by the American College of Obstetricians and Gynecologists. However, it is acknowledged that obstetricians are under some pressure to screen and treat for maternal subclinical hypothyroidism.
Indeed, several national endocrinology organizations recommend screening for and treatment of pregnant women for subclinical hypothyroidism. However, until there is demonstrable benefit for routine screening and treatment of subclinical hypothyroidism during pregnancy such practices are not recommended.
Isolated maternal hypothyroxinemia, defined as a normal range TSH with a low free-T4,has also been implicated in impaired fetal neurodevelopment. Specifically, offspring of Dutch women from an iodine-sufficient area and with isolated hypothyroxinemia defined by a free-T4 below the 10th percentile at 12 weeks gestation were reported to have significant developmental delay as measured by Bayley Scales of Infant Development.
However, low serum free-T4 levels with a paradoxically normal or even slightly decreased serum TSH are more classically suggestive of central hypothyroidism, which is a rare condition. Central hypothyroidism is most typically due to pituitary macroadenomas, pituitary surgery or irradiation. Isolated hypothyroxinemia also has been associated with iodine insufficiency due to an autoregulatory response by the thyroid gland that leads to an isolated low free-T4. Finally, laboratory inaccuracy from technical interference should also be considered when discordant thyroid test results are encountered.
When considering the impact of pregnancy on thyroid hormone levels and the increased pressure on obstetricians to screen for thyroid dysfunction during pregnancy, there will most certainly be an increase in the number of pregnant women identified with low free-T4 but normal TSH levels. Similar to subclinical hypothyroidism however, there are no reports indicating that treatment of such isolated hypothyroxinemia is beneficial for either the mother or her offspring.
In fact, the findings of the CATS study described above do not support treatment of subclinical thyroid disease during pregnancy. Therefore, screening for and treatment of women with isolated hypothyroxinemia is unwarranted and should be considered experimental.
The goal of treatment in pregnant women with overt hypothyroidism is clinical and biochemical euthyroidism. Levothyroxine sodium is the treatment of choice for routine management of hypothyroidism. The starting dose usually ranges from 1.0-2.0 µg/kg/day or approximately 100 µg/day. TSH is then measured at 6-8 week intervals and the levothyroxine dose is adjusted in 25-50 µg increments. The therapeutic goal is a TSH between 0.5 and 2.5 mU/L (see Figure 2).
Importantly, serum TSH values can be misleading during early therapy for hypothyroidism. This is because it takes 6 weeks or more for pituitary TSH secretion to re-equilibrate to the new thyroid hormone status. Assessment of free-T4 may be helpful when monitoring response to treatment.
Women with a history of hypothyroidism prior to conception should have a serum TSH evaluated at their first prenatal visit. Almost half of these women may, depending on the etiology of thyroid dysfunction, require an increase in thyroid replacement during pregnancy. Because of the increased likelihood of biochemical hypothyroidism during early pregnancy, some authors have recommended that the levothyroxine dose be routinely increased by 25-30% in pregnant women when the pregnancy is confirmed.
However, this practice has not been shown to be beneficial and there is a significant potential for overtreatment in such women. Thyroid treatment is best guided by thyroid function studies performed at initiation of prenatal care with consideration of the impact of pregnancy on thyroid analytes. In women with well-controlled thyroid disease, it is recommended that thyroid function studies be subsequently repeated during each trimester. Notably, several drugs can interfere with levothyroxine absorption (e.g. cholestyramine, ferrous sulfate, aluminum hydroxide antacids) or its metabolism (e.g. phenytoin, carbamazepine and rifampin).
4. Prognosis and outcome
After delivery, levothyroxine therapy should be returned to the prepregnancy dose and the TSH checked 6-8 weeks postpartum. Breastfeeding is not contraindicated in women treated for hypothyroidism. Levothyroxine is excreted into breast milk but levels are too low to alter thyroid function in the infant or to interfere with neonatal thyroid screening programs. Periodic monitoring with an annual serum TSH concentration is generally recommended given that changing weight and age may modify thyroid function.
Transient autoimmune thyroiditis has been identified in up to 10% of women during the first year after childbirth. Histologically, a destructive lymphocytic thyroiditis is identified. The likelihood of developing postpartum thyroiditis antedates pregnancy and is related to increasing serum levels of thyroid autoantibodies. For more information please go to the section on postpartum thyroiditis in Hyperthyroidism and Pregnancy.
5. What is the evidence for specific management and treatment recommendations
Dr Groot, L, Abalovich, M, Alexander, EK. “Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab. vol. 97. 2012. pp. 2543
Lazarus, JH, Bestwick, JP, Channon, S. “Antenatal thyroid screening and childhood cognitive function”. N Engl J Med. vol. 366. 2012. pp. 1650
Brent, GA. “The debate over thyroid-function screening in pregnancy”. N Engl J Med. vol. 366. 2012. pp. 562
Gyamfi, C, Wapner, RJ, D’Alton, ME. “Thyroid dysfunction in pregnancy: the basic science and clinical evidence surrounding the controversy in management”. Obstet Gynecol. vol. 113. 2009. pp. 702
Cleary-Goldman, J, Malone, FD, Lambert-Messerlian, G. “Maternal thyroid hypofunction and pregnancy outcome”. Obstet Gynecol. vol. 112. 2008. pp. 85
Casey, BM, Leveno, KJ. “Thyroid disease in pregnancy”. Obstet Gynecol. vol. 108. 2006. pp. 1283
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