Clinical Expert Series Continuing medical education is available online at www.greenjournal.org Thyroid Disease in Pregnancy Brian M. Casey, MD, and Kenneth J. Leveno, MD Thyroid testing during pregnancy should be performed on symptomatic women or those with a personal history of thyroid disease. Overt hypothyroidism complicates up to 3 of 1,000 pregnancies and is characterized by nonspecific signs or symptoms that are easily confused with complaints common to pregnancy itself. Physiologic changes in serum thyroid-stimulating hormone (TSH) and free thyroxine (T4) related to pregnancy also confound the diagnosis of hypothyroidism during pregnancy. If the TSH is abnormal, then evaluation of free T4 is recommended. The diagnosis of overt hypothyroidism is established by an elevated TSH and a low free T4. The goal of treatment with levothyroxine is to return TSH to the normal range. Overt hyperthyroidism complicates approximately 2 of 1,000 pregnancies. Clinical features of hyper- thyroidism can also be confused with those typical of pregnancy. Clinical hyperthyroidism is confirmed by a low TSH and elevation in free T4 concentration. The goal of treatment with thioamide drugs is to maintain free T4 in the upper normal range using the lowest possible dosage. Postpartum thyroiditis requiring thyroxine replacement has been reported in 2% to 5% of women. Most women will return to the euthyroid state within 12 months. (Obstet Gynecol 2006;108:1283–92) nterest in thyroid dysfunction complicating preg- would be identified if universal screening during Inancy has increased greatly during the past decade. pregnancy was adopted in the United States would This increased interest has been largely fueled by two have subclinical hypothyroidism.3 However, one of reports in 1999 that suggested offspring of women the most important U.S. Preventive Services Task with variously defined hypothyroidism identified dur- Force criteria for recommending screening of asymp- ing pregnancy, to include overt and subclinical dis- tomatic individuals is a demonstrated improvement in ease, are at increased risk of impaired neurodevelop- important health outcomes of those individuals iden- ment.1,2 There have also been reports linking tified through screening.6,7 The position of the Amer- subclinical hypothyroidism with an increased risk for ican College of Obstetricians and Gynecologists has preterm birth.3,4 As a result, several national endo- been that it is premature to recommend routine crine authorities have recommended routine screen- screening for subclinical hypothyroidism because 5 ing for hypothyroidism during pregnancy. The ratio- there is not good evidence that identification and nale for routine screening of pregnant women hinges treatment improves maternal or infant outcomes.8 on the reported prevalence of subclinical hypothy- Pregnancy is associated with significant but re- roidism and the potential benefits of treatment during versible changes in maternal thyroid physiology that pregnancy. Importantly, the majority of women who can lead to confusion in the diagnosis of thyroid abnormalities. First, there is moderate thyroid en- From the Department of Obstetrics and Gynecology, University of Texas largement as a result of pregnancy hormone–induced Southwestern Medical Center, Dallas, Texas. glandular hyperplasia and increased vascularity. Ul- Corresponding author: Brian M. Casey, MD, Department of Obstetrics and trasound evaluation of the thyroid gland during preg- Gynecology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9032; e-mail: [email protected]. nancy shows an increase in volume, whereas its echo structure remains unchanged.9 This enlargement, al- © 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. though not pathologic, may prompt biochemical eval- ISSN: 0029-7844/06 uation of thyroid status during pregnancy. As shown VOL. 108, NO. 5, NOVEMBER 2006 OBSTETRICS & GYNECOLOGY 1283 in Figure 1, there are well described changes in pregnancy has been associated with several preg- thyroid function tests during pregnancy that are re- nancy complications and intellectual impairment in lated to 1) an estrogen-mediated increase in circulat- offspring,12–15 it is currently less clear whether milder ing levels of thyroid-binding globulin, which is the forms of thyroid dysfunction have similar effects on major transport protein for thyroid hormone, 2) thy- pregnancy and infant outcomes.7 roid stimulation due to a “spillover” effect, especially in the first trimester, by hCG, which shares some OVERT HYPOTHYROIDISM structural homology with thyrotropin (TSH), and 3) a Overt hypothyroidism complicates between 1 of relative decline in availability of iodide related to 1,000 and 3 of 1,000 pregnancies and is characterized increased renal clearance and overall losses to the by vague, nonspecific signs or symptoms that are fetus and placenta.10 Further complicating the diagno- often insidious in onset and easily confused with sis of thyroid dysfunction during pregnancy are the complaints attributable to pregnancy itself. Initial effects that several abnormal pregnancy conditions symptoms include fatigue, constipation, cold intoler- such as gestational trophoblastic disease and hy- ance, and muscle cramps. These may progress to peremesis gravidarum have on thyroid function insomnia, weight gain, carpal tunnel syndrome, hair studies. loss, voice changes, and intellectual slowness. Women Especially relevant is the intimate relationship who report that such symptoms have worsened over between maternal and fetal thyroid function, particu- the previous year are more likely to have overt larly during the first half of pregnancy. The fetal thyroid disease.16 thyroid gland begins concentrating iodine and synthe- The most common cause of primary hypothy- sizing thyroid hormone after 12 weeks of gestation. roidism in pregnancy is chronic autoimmune thyroid- Any requirement for thyroid hormones before this itis. (Hashimoto’s thyroiditis) It is a painless inflam- time is supplied by the mother, and it is during this mation with progressive enlargement of the thyroid time that thyroid hormones are most important to gland characterized by diffuse lymphocytic infiltra- fetal brain development.11 However, significant fetal tion, fibrosis, parenchymal atrophy, and eosinophilic brain development continues considerably beyond change. Other important causes of primary hypothy- the first trimester, making thyroid hormone also roidism include endemic iodine deficiency and a important later in gestation. Importantly, although history of either ablative radioiodine therapy or thy- overt maternal thyroid failure during the first half of roidectomy. Secondary hypothyroidism is pituitary in origin. For example, Sheehan’s syndrome from a history of obstetric hemorrhage is characterized by pituitary ischemia and necrosis with subsequent defi- ciencies in some or all pituitary hormones. Other causes of secondary hypothyroidism include lympho- cytic hypophysitis and a history of a hypophysec- tomy. Tertiary or hypothalamic hypothyroidism is very rare. Central hypothyroidism refers to inade- quate stimulation of the thyroid gland because of a defect at the level of the pituitary or hypothalamus. Women with overt hypothyroidism are at an increased risk for pregnancy complications such as early pregnancy failure, preeclampsia, placental ab- ruption, low birth weight, and stillbirth (Table 1).12,13 Treatment of women with overt hypothyroidism has Fig. 1. The pattern of changes in serum concentrations of been associated with improved pregnancy outcomes. thyroid function studies and hCG according to gestational age. The shaded area represents the normal range of Diagnostic Approach thyroid-binding globulin, total thyroxine, thyroid-stimulat- The presence or absence of a pathologically enlarged ing hormone or free T in the nonpregnant woman.TBG, 4 thyroid gland (ie, goiter) depends on the cause of thyroid-binding globulin; T4, thyroxine; TSH, thyroid-stim- ulating hormone. Modified from Brent GA. Maternal thy- hypothyroidism. Women in areas of endemic iodine roid function: interpretation of thyroid function tests in deficiency or those with Hashimoto’s thyroiditis are pregnancy. Clin Obstet Gynecol 1997;40:3–15. much more likely to have a goiter. Other signs of Casey. Thyroid Disease in Pregnancy. Obstet Gynecol 2006. hypothyroidism include periorbital edema, dry skin, 1284 Casey and Leveno Thyroid Disease in Pregnancy OBSTETRICS & GYNECOLOGY Table 1. Pregnancy Complications in 96 Women nancy and highlight the need for gestational age– With Overt or Subclinical Hypothyroidism as specific TSH thresholds. Such thresholds have been 12,13,17 Reported by Davis, Leung, and Their Colleagues reported and are based on a large population-based Hypothyroidism (%) study of pregnant women.21 As shown in Figure 2, the upper limit of the statistically defined normal range Overt Subclinical for TSH (97.5th percentile) in the first half of preg- (57؍n) (39؍Complications (n nancy was 3.0 milliunits/L.21 Moreover, if population- Preeclampsia 12 (31) 9 (16) specific medians for TSH are determined for each Abruptio placentae 3 (8) 0 (0) trimester at a particular laboratory, these data indicate Postpartum hemorrhage 4 (10) 1 (2) Cardiac dysfunction 1 (3) 1 (2) the upper limit of TSH during the first trimester Birth weight less than 2,000 g 10 (26) 6 (11) should be 4.0 multiples of the median