Thyroid Disease in Pregnancy

Clinical Expert Series

Continuing medical education is available online at www.greenjournal.org

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 hyperthyroidism 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 lymphocytic 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-stimulating 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 and 2.5 multi- Stillbirths 3 (8) 1* ples of the median for the second and third trimester Data are n (%). in singleton gestations. The upper limit for twin * Due to syphilis. gestations should be 3.5 multiples of the median in the first trimester and 2.5 multiples of the median in the second and third trimesters.21 and prolonged relaxation phase of deep tendon re- The effects of changes in free T4 levels during flexes. The diagnosis of clinical hypothyroidism dur- normal pregnancy have been the subject of much ing pregnancy is particularly difficult because many of controversy, particularly with the advent of auto- the signs or symptoms listed above are also common mated free hormone immunoassays. The diagnostic to pregnancy. Thyroid testing should be performed accuracy of these free T4 tests are dependent on on symptomatic women or those with a personal protein binding, especially given the physiologic history of thyroid disease.8 changes in thyroid-binding globulin and other pro- The mainstay for the diagnosis of thyroid disease teins during pregnancy.22 (Fig. 1) Although there is a is the measurement of serum TSH. Serum TSH is significant decrease in free T4 in late gestation when more sensitive than free T4 for detecting hypothyroid- compared with nonpregnant women or those in the ism and hyperthyroidism. If the TSH is abnormal, first trimester, overall, free T4 concentrations remain then evaluation of free T4 is recommended. A disad- within the reference range (0.7–1.8 ng/dL) through- vantage of this TSH-first testing strategy is that un- out pregnancy.10 Therefore, we recommend using usual thyroid conditions characterized by discordant nonpregnant free T4 thresholds for diagnosis of hypo- 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 nonpregnant individuals is 0.45–4.5 milliunits/L. However, recent data indicates that more than 95% of normal individuals have a TSH level below 2.5 milliunits/L and that those with a TSH between 2.5 and 4.5 milliunits/L have an increased risk of progression to overt disease.18 This has led some to recommend a decrease in the upper limit of the TSH reference range to 2.5 milli-international units/L19, whereas others suggest that this change would only increase the diagnosis of subclinical hypothyroidism without clear evidence of a benefit from Fig. 2. Gestational age–specific thyroid stimulating hor- 20 treatment. We are therefore of the view that a mone (TSH) nomogram derived from 13,599 singleton and reduction in the upper limit of normal for TSH is 132 twin pregnancies as reported by Dashe and col- currently unwarranted. leagues.21 TSH, thyroid-stimulating hormone. Modified During early pregnancy there is a fall in serum from Dashe JS, Casey BM, Wells CE, McIntire DD, Byrd EW, Leveno KJ, Cunningham FG. Thyroid-stimulating hor- TSH and a modest increase in free thyroxine because mone in singleton and twin pregnancy: importance of of the structurally related thyroid-stimulating activity gestational age–specific reference ranges. Obstet Gynecol of hCG.10 (Fig. 1) These physiologic changes con- 2005;106:753–7. Copyright © 2005 by ACOG. found the diagnosis of hypothyroidism during preg- Casey. Thyroid Disease in Pregnancy. Obstet Gynecol 2006.

VOL. 108, NO. 5, NOVEMBER 2006 Casey and Leveno Thyroid Disease in Pregnancy 1285 thyroidism until pregnancy-specific free T4 thresholds are available. Finally, it may 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 thyroid dysfunction, and progression to symptomatic disease.23,24 One recent study revealed that 50% of women identified with thyroid peroxidase antibodies at 16 weeks gestation devel- oped postpartum thyroid dysfunction and one in four of these women went on to develop permanent overt hypothyroidism within the year.25

Therapeutic Approach The goal of treatment in pregnant women with overt hypothyroidism is clinical and biochemical euthy- roidism. Levothyroxine sodium is the treatment of choice for routine management of hypothyroidism. The starting dose usually ranges from 1.0–2.0 ␮g/ kg/d or approximately 100 ␮g/d. Thyroid-stimulating hormone is then measured at 6–8 week intervals, and ␮ the levothyroxine dose is adjusted in 25- to 50- g Fig. 3. Management algorithm for pregnant women with a increments. The therapeutic goal is a TSH between history of hypothyroidism or those newly diagnosed during 0.5 and 2.5 milliunits/L.26 (Fig. 3) Importantly, as pregnancy. shown in Figure 4, serum TSH values can be mislead- Casey. Thyroid Disease in Pregnancy. Obstet Gynecol 2006. ing during early therapy for hypothyroidism. This is because it takes 6 weeks or more for pituitary TSH secretion to reequilibrate to the new thyroid hormone Follow-up

status. Assessment of free T4 may be helpful when After delivery, levothyroxine therapy should be re- monitoring response to treatment. turned to the prepregnancy dose and the TSH Women with a history of hypothyroidism before checked 6 to 8 weeks postpartum. Breastfeeding is not conception should have a serum TSH evaluated at contraindicated in women treated for hypothyroid- their first prenatal visit. Almost half of these women ism. Levothyroxine is excreted into breast milk but will require an increase in thyroid replacement during levels are too low to alter thyroid function in the pregnancy. Because of the increased likelihood of infant or to interfere with neonatal thyroid screening biochemical hypothyroidism during early pregnancy, programs.28 Periodic monitoring with an annual se- some authors have recommended that the levothy- rum TSH concentration is generally recommended, roxine dose be routinely increased by 30% in preg- given that changing weight and age may modify nant women at the time that pregnancy is con- thyroid function. firmed.27 However, this practice has not been shown to be beneficial, and because there is a significant SUBCLINICAL HYPOTHYROIDISM potential for overtreatment in such women, we be- Reports suggesting increased fetal wastage or subse- lieve that thyroid treatment should be guided by quent neurodevelopmental complications in the off- thyroid function studies performed at initiation of spring of women with mild hypothyroidism have prenatal care.16 In women with well-controlled thy- prompted recommendations that levothyroxine be roid disease, it is recommended that thyroid function prescribed to restore the TSH level to the reference studies be repeated during each trimester. Notably, range.5 However, there are no published intervention several drugs can interfere with levothyroxine absorp- trials specifically assessing the efficacy of such treat- tion (eg, cholestyramine, ferrous sulfate, aluminum ment to improve neuropsychological performance in hydroxide antacids) or its metabolism (eg, phenytoin, offspring of women with subclinical hypothyroidism

carbamazepine, and rifampin). (ie, elevated TSH and normal free T4). As a result,

1286 Casey and Leveno Thyroid Disease in Pregnancy OBSTETRICS & GYNECOLOGY Fig. 4. Thyroid-stimulating hormone and free thyroxine values during tran- sition periods after treatment for hyperthyroidism or hypothyroidis- m.ATD, antithyroid drugs; RAI, radioactive iodine; TSH, thyroid- stimulating hormone; FT4, free thyroxine. Reproduced with permission of the National Academy of Clinical Biochemistry, Washington, DC. Lab- oratory medicine practice guidelines: laboratory support for the diagnosis of thyroid disease. Larchmont (NY): Mary Ann Liebert; 2003. Casey. Thyroid Disease in Pregnancy. Obstet Gynecol 2006. routine screening and treatment of subclinical hypo- When considering the impact of pregnancy on thyroidism during pregnancy is not recommended by thyroid hormone status (Fig. 1) and the increased pres- the American College of Obstetricians and Gynecol- sure on obstetricians to screen for thyroid dysfunction ogists. It is acknowledged however, that obstetricians during pregnancy, there will likely be an increase in the are under increasing pressure to screen and treat for number of pregnant women identified with low free T4 maternal subclinical hypothyroidism despite uncer- but normal TSH levels. Similar to subclinical hypothy- tainty whether such therapy would be beneficial. roidism, however, there are no reports indicating that Indeed, national endocrinology organizations have treatment of such isolated hypothyroxinemia is benefi- emphasized the need for large clinical trials to address cial for the either mother or her offspring. Therefore, we this issue. Until such studies are complete, we con- believe that treatment of such women, in the absence of tinue to recommend against routine screening for and central hypothyroidism, is unwarranted and should be treatment of subclinical hypothyroidism during considered experimental. pregnancy. OVERT HYPERTHYROIDISM ISOLATED HYPOTHYROXINEMIA Overt hyperthyroidism complicates approximately 2 Maternal isolated hypothyroxinemia, defined as a nor- of 1,000 of pregnancies. Pregnant women with hyper- mal range TSH with a low free T4, has recently been thyroidism are at increased risk for spontaneous preg- implicated in impaired fetal neurodevelopment.2,11 Spe- nancy loss, congestive heart failure, thyroid storm, cifically, offspring of Dutch women from an iodine- preterm birth, preeclampsia, fetal growth restriction, sufficient area and with isolated hypothyroxinemia de- and associated increased perinatal morbidity and 31,32 fined by a free T4 below the 10th percentile at 12 weeks mortality. (Table 2) The most common cause of of gestation were reported to have significant develop- overt hyperthyroidism is Graves’ disease, an organ- mental delay as measured by Bayley Scales of Infant specific autoimmune process whereby thyroid-stimu- 2,29 Development. Low serum free T4 levels with a para- lating autoantibodies attach to and activate TSH doxically normal or even slightly decreased serum TSH receptors. In pregnant women with a history of are classically suggestive of central hypothyroidism, Graves’ disease, however, thyroid-stimulating anti- which is a rare condition. Central hypothyroidism is body activity may actually decline, leading to chem- most typically due to pituitary macroadenomas, pitu- ical remission during pregnancy.33 Other causes of itary surgery, or irradiation. Isolated hypothyroxinemia overt hyperthyroidism include functioning adenoma has also been associated with iodine insufficiency due to or toxic nodular goiter, thyroiditis, and excessive an autoregulatory response by the thyroid gland that thyroid hormone intake. 30 leads to an isolated low free T4. Finally, laboratory There is a unique form of hyperthyroidism asso- inaccuracy from technical interference should also be ciated with pregnancy called gestational transient thyro- considered when discordant thyroid test results are toxicosis. It is typically associated with hyperemesis encountered.22 gravidarum, and can be due to high levels of hCG

VOL. 108, NO. 5, NOVEMBER 2006 Casey and Leveno Thyroid Disease in Pregnancy 1287 Table 2. Pregnancy Outcomes in 239 Women when diagnosing hypothyroidism during pregnancy, With Overt Hyperthyroidism as Reported one must consider the impact of gestational age on by Davis, Kriplani, Millar, and Their measurement of TSH. For example, the 2.5th percen- 12,31,34 Colleagues tile for TSH during the first half of pregnancy in one Treated and Uncontrolled study fell below 0.1 milliunits/L.21 Despite the effect Euthyroid Thyrotoxicosis of pregnancy on maternal thyroxine levels, use of (90؍n) (149؍Factor (n nonpregnant fT4 thresholds is recommended (0.7–1.8 Maternal outcome ng/dL). Rarely, symptomatic hyperthyroidism is Preeclampsia 17 (11) 15 (17) caused by an abnormally high serum T3 in women Heart failure 1 7 (8) with a normal free T (T thyrotoxicosis). In women with Death 0 1 4 3 Perinatal outcome depressed TSH yet normal free T4, evaluation of free Preterm delivery 12 (8) 29 (32) T3 or the T3 index may explain the presence of Growth restriction 11 (7) 15 (17) hypermetabolic symptoms. Evaluation of TSH recep- Stillborn 0/59 6/33 (18) tor antibodies has also been shown to be helpful in Thyrotoxicosis 1 2 assessing women with Graves’ disease and may be Hypothyroid 4 0 Goiter 2 0 associated with delivery of an infant with hypothyroidism.35,36 Data are n (%). Therapeutic Approach resulting from molar pregnancy. These high hCG Treatment of hyperthyroid women to achieve ade- levels lead to TSH receptor stimulation and tempo- quate metabolic control has been associated with rary hyperthyroidism. Women with gestational tran- improved pregnancy outcome.31,32,34 (Fig. 5) Thyro- sient thyrotoxicosis are rarely symptomatic and treat- toxicosis during pregnancy can nearly always be ment with antithyroxine drugs has not been shown to controlled by thioamide drugs. Some clinicians prefer be beneficial. With expectant management of hy- propylthiouracil because it partially inhibits the con- peremesis gravidarum, serum free T4 levels usually version of T4 to T3 and crosses the placenta less normalize in parallel with the decline in hCG concen- readily than methimazole. Although not proven, me- trations as pregnancy progresses beyond the first thimazole used in early pregnancy has been associ- trimester. Notably, TSH levels may remain partially ated with esophageal and choanal atresia as well as 37–39 depressed for several weeks after free T4 levels have aplasia cutis in the fetus. Transient leukopenia returned to the normal range. Gestational transient occurs in about 10% of pregnant women treated with thyrotoxicosis has not been associated with poor thioamides but usually does not require cessation of pregnancy outcomes. therapy. In approximately 0.2% of women, agranulocytosis develops suddenly and mandates discontinu- Diagnostic Approach ation of the drug. Agranulocytosis is not dose related, As with hypothyroidism, clinical features of hyperthy- and because of its acute onset, serial leukocyte counts roidism can be easily confused with those typical of during therapy have not been helpful in prevention. pregnancy. Suggestive complaints include nervous- Therefore, women given thioamide drugs should ness, heat intolerance, palpitations, thyromegaly or discontinue medication immediately if they develop a goiter, failure to gain weight or weight loss, and fever or sore throat until complete evaluation for exophthalmos. Although nausea is common in early agranulocytosis can be performed. pregnancy, the occurrence of hyperemesis gravida- The dose of thioamide is empirical. In nonpreg- rum together with weight loss can signify overt hy- nant women, the American Thyroid Association rec- perthyroidism. Thyroid testing may be beneficial in ommends an initial daily dose of 100 mg to 600 mg these circumstances. Otherwise, routine testing in for propylthiouracil or 10 mg to 40 mg for methima- women with hyperemesis gravidarum is not zole.40 It has been our experience that women with recommended. overt hypothyroidism diagnosed during pregnancy The diagnosis of overt hyperthyroidism can be require a higher average daily propylthiouracil dose, reliably confirmed by evaluating serum TSH and free and we recommend a starting dosage of at least 300

T4. In women with a depressed serum TSH level (less mg each day. The goal of treatment during pregnancy than 0.45 milli-international units/L), clinical hyper- is to maintain free T4 in the upper normal range using 41 thyroidism is confirmed by an elevation in fT4 (more the lowest possible dose of thioamide. Improvement than 1.8 ng/dL) concentration. However, as is true in free T4 levels is generally seen in 4 weeks, and the

1288 Casey and Leveno Thyroid Disease in Pregnancy OBSTETRICS & GYNECOLOGY hydration, and delirium or coma. Thyroid storm is rare in pregnancy and its diagnosis is based entirely on clinical grounds in women with laboratory tests consistent with overt hyperthyroidism. Heart failure due to cardiomyopathy from excessive thyroxine in women with uncontrolled hyperthyroidism is more common in pregnant women.46 Treatment of thyroid storm or thyrotoxic heart failure is similar. They both should be treated as medical emergencies in an intensive care setting47 Specific treatment consists of 1g of propylthiouracil given orally or crushed and placed through a naso- gastric tube. This drug is continued in 200-mg doses every 6 hours. An hour after initial propylthiouracil

dosing, iodide is given to inhibit thyroid release of T3 and T4. It is given every eight hours as 500 mg to 1,000 mg of intravenous sodium iodide, or it can be given orally as five drops of supersaturated solution of potassium iodide or as 10 drops of oral Lugol’s solution every 8 hours. If there is a history of iodine- induced anaphylaxis, lithium carbonate, 300 mg every 6 hours, is given instead.48 Most authorities also recommend dexamethasone be given intravenously Fig. 5. Management algorithm for pregnant women with a as 2 mg every 6 hours for four doses to further block history of hyperthyroidism or those newly diagnosed during peripheral conversion of T to T . Treatment with a pregnancy. 4 3 ␤-blocker to control tachycardia is usually reserved Casey. Thyroid Disease in Pregnancy. Obstet Gynecol 2006. for heart rates of 120 beats per minute or higher. Propranolol, labetalol, and esmolol have all been median time to normalization of the TSH concentra- used successfully in pregnancy.49 tion is 6 weeks to 8 weeks.42,43 Importantly, caution against overtreatment is recommended because it Follow-up may result in maternal or fetal hypothyroidism. Serial Women with Graves’ disease should be followed up ultrasound assessment of fetal thyroid size to assist in closely after delivery, because recurrence or aggrava- management of pregnant women taking thioamide tion of symptoms is not uncommon in the first few drugs has been reported.35,43 However, routine ultra- months postpartum. Most asymptomatic women sonic evaluation of the fetal thyroid is currently not should have a TSH and free T4 performed approxi- recommended. mately 6 weeks postpartum. Both propylthiouracil There are other alternatives for treatment of overt and methimazole are excreted in breast milk, but hyperthyroidism that are rarely undertaken during propylthiouracil is largely protein bound and does not pregnancy. For example, thyroidectomy is typically seem to pose a significant risk to the breastfed infant. reserved for treatment outside of pregnancy. Occa- Methimazole has been found in breastfed infants of sionally however, women who cannot adhere to treated women in amounts sufficient to cause thyroid medical therapy or in whom therapy is toxic may dysfunction. However, at low doses (10–20 mg/d) it benefit from surgical management.44 Ablative radio- does not seem to pose a major risk to the nursing active iodine is contraindicated in pregnancy because infant.50 The American Academy of Pediatricians it can destroy the fetal thyroid. It has been recom- considers both compatible with breastfeeding.51 mended that women avoid pregnancy for a period of 6 months after radioablative therapy.45 SUBCLINICAL HYPERTHYROIDISM Subclinical hyperthyroidism is defined as a serum Thyroid Storm or Heart Failure TSH concentration below the statistically defined

Thyroid storm is an acute, life-threatening exacerba- lower limit of the reference range when serum free T4 tion of thyrotoxicosis. The classic findings are fever, and free T3 concentrations are within their reference tachycardia, tremor, nausea, vomiting, diarrhea, de- range.7 Subclinical hyperthyroidism affects 1.7% of

VOL. 108, NO. 5, NOVEMBER 2006 Casey and Leveno Thyroid Disease in Pregnancy 1289 pregnant women and is more frequently diagnosed ides are typically ineffective, and approximately two with the use of extremely sensitive, third-generation thirds of these women return to a euthyroid state. If serum TSH assays.52 Its prevalence is higher in io- symptoms are severe, however, a ␤-blocker may be dine-insufficient areas and increases with age. Sub- given. Between 4 and 8 months postpartum, 2% to 5% clinical hyperthyroidism has been reported to have of women develop hypothyroidism.53,59 Importantly, long-term adverse sequelae that include osteoporosis, hypothyroidism can even develop within 1 month of cardiovascular morbidity, and progression to overt the onset of thyroiditis. Thyromegaly and other symp- thyrotoxicosis or thyroid failure. During pregnancy, toms are common and more prominent than during however, the diagnosis of subclinical hyperthyroidism the thyrotoxic phase. Thyroxine replacement is rec- has not been found to be associated with adverse ommended for at least 6 months to 12 months. Most outcomes.52 In fact, subclinical hyperthyroidism may women identified with postpartum thyroiditis will even have a protective effect against development of return to the euthyroid state within 12 months of 52 hypertension during pregnancy. delivery. Women who experience either type of At present there is no convincing evidence that postpartum thyroiditis have about a 30% risk of subclinical hyperthyroidism should be treated in non- developing permanent hypothyroidism.60,25 pregnant individuals. Therefore, treatment during pregnancy seems especially unwarranted because maternal antithyroid drugs cross the placenta. Further REFERENCES 1. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, studies are necessary to ascertain whether there are Gagnon J, et al. 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