FIRST OF 2 PARTS

Annette E. Bombrys, DO How to manage hypothyroid Dr. Bombrys is a Fellow in Maternal– Fetal Medicine, Department of and Gynecology, at the disease in University of Cincinnati College of Medicine in Cincinnati, Ohio. Pregnancy complicated by puts Mounira A. Habli, MD Dr. Habli is a Fellow in Maternal– mother and at risk—symptoms or otherwise Fetal Medicine, Department of Obstetrics and Gynecology, at the University of Cincinnati College of pregnant woman whose tion is controlled by a negative-feedback Medicine in Cincinnati, Ohio. gland isn’t doing its job presents loop that works like this: Baha M. Sibai, MD Dr. Sibai is Professor, Department A a serious management problem • The hypothalamus releases thyroid- of Obstetrics and Gynecology, at for her obstetrician. If she has overt hy- releasing hormone (TRH) the University of Cincinnati College pothyroidism, seen in between 0.3% and • TRH acts on the pituitary gland to of Medicine in Cincinnati, Ohio. 2.5% of , active intervention release thyroid-stimulating hormone The authors report no fi nancial ® Dowden Health Media relationships relevant to this article. is required to prevent serious damage to (TSH) the fetus.1,2 Even if she has subclinical • TSH, in turn, acts on the , seen in 2% toCopyright 3% of pregnan-For personalgland to release use the only thyroid hormones cies, current research indicates that inter- iodothyronine (T3) and thyroxine (T4) vention may be indicated. that regulate metabolism Fetal thyroxine requirements increase • TRH and TSH concentrations are in-

as early as 5 weeks of gestation, when the versely related to T3 and T4 concen- IN THIS ARTICLE fetus is still dependent on maternal thy- trations. That is, the more TRH and roxine. A defi ciency of maternal thyrox- TSH circulating in the stream, ❙ Which pregnant

ine can have severe adverse outcomes, the less T3 and T4 will be produced by women to screen? affecting the course of the pregnancy the thyroid gland3 Page 30 and the neurologic development of the • Almost all (approximately 99%) cir-

fetus. To prevent such sequelae, patients culating T3 and T4 is bound to a pro- ❙ Causes reviewed who were on thyroid medication before tein called thyroxine-binding globulin Page 33 pregnancy should increase the dosage by (TBG). Only 1% of these hormones 30% once pregnancy is confi rmed, and circulate in the free form, and only the ❙ Fetal and neonatal hypothyroidism that develops in preg- free forms are biologically active.3 consequences nancy should be managed aggressively This relationship is illustrated in Page 34 and meticulously. FIGURE 1 (page 30). Here, we’ll examine the published re- search to advise you on evidence-based Pregnancy reduces free forms of T3 approaches for diagnosis and manage- and T , and increases TSH slightly 4 Coming in ment of this complex condition. Pregnancy alters thyroid function in sig- nifi cant ways: FEBRUARY • Increases in circulating estrogen lead In Part 2 of this series, Maternal thyroid function to the production of more TBG Dr. Bombrys, Dr. Habli, and Dr. Sibai review An elaborate negative-feedback • When TBG increases, more T3 and loop prevails before pregnancy T are bound and fewer free forms of in 4 pregnancy In a nonpregnant woman, thyroid func- these hormones are available

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29_r1_OBGM0108 29 12/19/07 6:46:29 PM Hypothyroid disease in pregnancy

FIGURE 1 should be monitored using free T4 Thyroid physiology (FT4) and TSH levels and the impact of pregnancy • Increased TBG also leads to a slight increase in TSH between the fi rst trimester and term Hypothalamus • Human chorionic gonadotro- pin (hCG) concentrations also increase in pregnancy. Because Pregnancy causes: Thyroid-releasing hormone hCG has thyrotropin-like activity, üthyroxine-binding globulin and these higher levels cause a tran- †free hormones sient decrease in TSH by suppres- (T3, T4), Pituitary sion of TSH production between leading to… approximately 8 and 14 weeks of gestation. Thyroid-stimulating hormone üHuman chorionic gonadotropin, Fetal thyroid function which transiently Thyroid suppresses During early gestation, the fetus re- production of … ceives thyroid hormone from the mother.1 Maternal T crosses the pla- T (iodothyronine) 4 3 centa actively—the only hormone that and T (thyroxine) 4 does so.4 The fetus’s need for thyroxine starts to increase as early as 5 weeks of gestation.5 Fetal thyroid development does not TABLE 1 begin until 10 to 12 weeks of gestation, Distinguishing hypothyroidism from and then continues until term. The fetus a normal gestation can be challenging relies on maternal T4 exclusively before 12 weeks and partially thereafter for SYMPTOM HYPOTHYROIDISM PREGNANCY normal fetal neurologic development. It Fatigue • • follows that maternal hypothyroidism could be detrimental to fetal develop- Constipation • • ment if not detected and corrected very Hair loss • early in gestation.

Dry skin •

Brittle nails • How (and whom) to screen for maternal hypothyroidism Weight gain • • Routine screening has been recom- Fluid retention • • mended for women who have infer- tility, menstrual disorders, or type 1 Bradycardia • • diabetes mellitus, and for pregnant Goiter • women who have of defi cient thyroid function.6 In recent Carpal tunnel syndrome • • years, some authors have recommend- ed screening all pregnant women for

• Because the total T3 (TT3) and to- thyroid dysfunction, but such recom- 3,7,8 tal free T4 (TT4) are decreased in mendations remain controversial. pregnancy, they are not good mea- Routine screening is not endorsed by sures of thyroid function. Mater- the American College of Obstetricians nal thyroid function in pregnancy and Gynecologists.6

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30 OBG MANAGEMENT • January 2008

30_r1_OBGM0108 30 12/20/07 12:26:52 PM Hypothyroid disease in pregnancy

Symptoms overlap typical TABLE 2 conditions of pregnancy Laboratory diagnosis of hypothyroidism The diffi culty here is that the character- istic signs and symptoms of hypothy- MATERNAL CONDITION TSH FREE T FREE T TOTAL T TOTAL T roidism are very similar to physiologic 3 4 3 4 conditions seen in most pregnancies. Normal No No ü ü ü They include fatigue, constipation, cold pregnancy change change intolerance, muscle cramps, hair loss, dry Hypothyroidism ü † † † † skin, brittle nails, weight gain, intellec- tual slowness, bradycardia, depression, Subclinical ü No No † † hypothyroidism change change insomnia, periorbital , , 6 and .6 A side-by-side Adapted from American College of Obstetricians and Gynecologists comparison of pregnancy conditions and hypothyroidism symptoms is provided in TABLE 3 TABLE 1 (page 30). Causes of hypothyroidism Which laboratory tests Iodine defi ciency are informative? Hashimoto’s Because screening is controversial and symptomatology does not reliably distin- Radioactive iodine therapy

guish hypothyroidism from normal preg- Thyroidectomy nancy, laboratory tests are the standard for diagnosis. Overt hypothyroidism is Viral thyroiditis

diagnosed in a symptomatic patient by Sheehan’s syndrome elevated TSH level and low levels of FT4 Medications and free T3 (FT3). Subclinical hypothy- roidism is defi ned as elevated TSH with • Thionamides • Lithium normal FT4 and FT3 in an asymptomatic • Drugs that inhibit absorption of patient. Level changes characteristic of thyroid medication FAST TRACK normal pregnancy, overt hypothyroid- - Ferrous sulfate Characteristic signs ism, and subclinical hypothyroidism are - Sucrafate - Cholestyramine and symptoms given in TABLE 2.6 - Antacids (aluminum hydroxide) of hypothyroidism resemble physiologic What causes a condition we will discuss in Part 2 of conditions typically hypothyroidism? this series in February; thyroidectomy; vi- seen in pregnancy The most common cause of hypothyroid- ral thyroiditis; pituitary tumors; Sheehan’s ism in most of the world is iodine defi - syndrome; and a number of medications. ciency. In developed countries, however, Causes of hypothyroidism are sum- where lack of iodine in the diet is not a marized in TABLE 3.3 problem, Hashimoto’s thyroiditis, also known as chronic autoimmune thyroid- Effects vary by medication itis, is the most common cause. Hashi- Medications alter thyroid function in dif- moto’s thyroiditis is characterized by ferent ways. Iodine and lithium inhibit thy- the presence of antithyroid , roid function and, along with dopamine including both thyroid antimicrosomial antagonists, increase TSH levels. Converse- and antithyroglobulin antibodies. Both ly, thioamides, glucocorticoids, dopamine iodine defi ciency and Hashimoto’s thy- agonists, and somatostatins decrease TSH roiditis are associated with goiter.5 Other levels. Finally, ferrous sulfate, sucrafate, causes of hypothyroidism include radio- cholestyramine, and aluminum hydrox- active iodine therapy for Graves’ disease, ide antacids all inhibit gastrointestinal

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TABLE 4 intrauterine fetal demise and still- Fetal and neonatal effects of birth, preterm delivery, low birth asymptomatic overt hypothyroidism weight, preeclampsia, and develop- mental anomalies including reduced STUDY LABORATORY OUTCOMES AND intelligence quotient (IQ).1,2,4,6 Blazer FINDINGS RECOMMENDATIONS and colleagues correlated intrauterine 12 Kooistra et al † FT4 Maternal hypothyroxinemia is a risk growth with maternal TSH and fe- for neurodevelopmental abnormalities tal FT and concluded that impaired as early as 3 weeks of age 4 intrauterine growth is related to ab- Casey et al10 ↑ TSH Pregnancies with undiagnosed normal thyroid function and might subclinical hypothyroidism were refl ect an insuffi cient level of hormone more likely to be complicated by and . production by hypothyroid mothers 9 The reduced IQ seen in a prior study during pregnancy. Maternal and con- (Mitchell and Klein4) may be related to genital hypothyroidism resulting from effects of prematurity severe iodine defi ciency are associated Mitchell and ü TSH The mean and standard deviation with profound neurologic impairment Klein4 of IQs of the children of treated and mental retardation.1,3,10 If the mothers with hypothyroidism and the condition is left untreated, cretinism control group were signifi cantly higher can occur. Congenital cretinism is as- than those for children of untreated hypothyroid women sociated with growth failure, mental retardation, and other neuropsycho- Blazer et al9 ü maternal TSH, Impaired intrauterine growth may logic defi cits including deaf-mutism.3,4 ü fetal FT4 refl ect insuffi cient levels of hormone replacement therapy in hypothyroid However, if cretinism is identifi ed and mothers during pregnancy treated in the fi rst 3 months of life, near-normal growth and intelligence 7 Pop et al † FT4 Impaired psychomotor development can be expected.6 For this reason, all at 10 months of age in offspring of 50 states and the District of Columbia mothers with low T4 at ≤12 weeks require newborn screening for con- 8 Haddow et al ü TSH, † FT4 Elevated TSH levels at <17 weeks’ genital hypothyroidism.6 gestation are associated with low IQ Asymptomatic overt hypothyroidism. scores at 7 to 9 years of age. Routine • screening for thyroid defi ciency may Several studies have evaluated neonatal be warranted outcomes in pregnancy complicated by asymptomatic overt hypothy- Klein et al11 ü TSH, † FT , Inverse correlation between TSH 4 roidism—that is, women who had † TT4 during pregnancy and IQ of offspring previously been diagnosed with hy- FT = free thyroxine, TSH = thyroid-stimulating hormone, TT = total thyroxine 4 4 pothyroidism, who have abnormal

TSH and FT4 levels, but who do not have symptoms. Pop and colleagues absorption of thyroid hormone and have shown impaired psychomotor therefore should not be taken within 4 development at 10 months in infants 6 hours of thyroid medication. born to mothers who had low T4 dur- ing the fi rst 12 weeks of gestation.7 Haddow and colleagues correlated Maternal hypothyroidism: elevated maternal TSH levels at less Effects on fetus, newborn than 17 weeks’ gestation with low The impact of maternal hypothyroidism IQ scores in the offspring at 7 to 9 on the fetus depends on the severity of years of age.8 Klein and colleagues the condition. demonstrated an inverse correla- • Uncontrolled hypothyroidism. The tion between a woman’s TSH level consequences of this condition can during pregnancy and the IQ of her be dire. The possibilities include offspring.11 Kooistra and colleagues

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34 OBG MANAGEMENT • January 2008 Hypothyroid disease in pregnancy

confi rmed that maternal hypothyrox- FIGURE 2 inemia is a risk for neurodevelopmen- During pregnancy, thyroid function merits tal abnormalities that can be identifi ed regular monitoring, fi ne-tuning of treatment as early as 3 weeks of age.12 Studies of this relationship are summarized in TABLE 4 (page 34). Patient with history • Subclinical hypothyroidism. During of hypothyroidism the past decade, researchers have fo- cused attention on neonatal neurologic + hCG/home pregnancy test function in infants born to mothers Increase who had subclinical disease. Mitchell dosage and Klein evaluated the prevalence of by 30% subclinical hypothyroidism at less than 17 weeks’ gestation and subsequently compared the IQs in these children Laboratory test: TSH and FT with those of controls.4 They found the 4 mean and standard-deviation IQs of the children in the control and treated TSH between 1 and groups to be signifi cantly higher than TSH and FT4 abnormal 2 mU/L and FT4 in those of the children whose mothers upper third of normal were not treated. Casey and colleagues evaluated pregnancy outcomes in women who had undiagnosed subclini- Adjust levothyroxine in 10 25-μg increments Monitor TSH and FT4 cal hypothyroidism. They found that every trimester such pregnancies were more likely to be Abnormal complicated by placental abruption and Monitor TSH and FT preterm birth, and speculated that the 4 Normal reduced IQ demonstrated in the Mitch- every 4 weeks ell and Klein study might have been re- lated to the effects of prematurity. every trimester until delivery. FIGURE 2 provides an algorithm for management Managing hypothyroidism of hypothyroidism in pregnancy. in pregnancy The treatment of choice for correction of hypothyroidism is synthetic T4, or le- Postpartum thyroiditis vothyroxine (Levothyroid, Levoxyl, Syn- About 5% of all obstetrical patients de- throid, and Unithroid). Initial treatment velop postpartum thyroiditis. Approxi- in the nonpregnant patient is 1.7 μg/kg/ mately 45% of these women present with day or 12.5 to 25 μg/day adjusted by 25 hypothyroidism, with the rest evenly di- μg/day every 2 to 4 weeks until a euthy- vided between thyrotoxicosis (hyperthy- roid state is achieved.13 roidism) and thyrotoxicosis followed by Patients who were on thyroxine hypothyroidism. Unfortunately, the signs therapy before pregnancy should in- and symptoms of hypo- and hyperthy- crease the dose by 30% once pregnancy roidism are similar to the postpartum is confi rmed.1,5 Serum thyrotropin levels state. Many of these patients are not di- should be monitored every 4 weeks to agnosed. A high index of suspicion war- maintain a TSH level between 1 and 2 rants thyroid function testing. Women 1 mU/L and FT4 in upper third of normal. who have a history of Once a euthyroid state has been achieved, mellitus have a 25% chance of develop- thyrotropin levels should be monitored ing postpartum thyroid dysfunction.

CONTINUED www.obgmanagement.com January 2008 • OBG MANAGEMENT 37 Hypothyroid disease in pregnancy

The diagnosis is made by document- References 1. Idris I, Srinivasan R, Simm A, Page RC. Effects of ing abnormal levels of TSH and FT4. maternal hyperthyroidism during early gestation on Postpartum hyperthyroidism may be neonatal and obstetric outcome. Clin Endocrinol. diagnosed by the presence of antimicro- 2006;65:133–135. somal or thyroperoxidase antithyroid 2. Girling JC. Thyroid disorders in pregnancy. Curr Ob- peroxidase antibodies. Goiter may be stet Gynecol. 2006;16:47–53. present in up to 50% of patients. 3. Creasy RK, Resnik R, Iams J. Maternal–Fetal Medi- cine. 5th ed. Philadelphia, Pa: Saunders Elsevier; 2004:1063–1082. Postpartum thyroiditis 4. Mitchell ML, Klein RZ. The sequelae of untreated has two phases maternal hypothyroidism. Eur J Endocrinol. 2004;151 Suppl 3:U45–U48. The fi rst phase, also known as the thyro- 5. Alexander EK, Marqusee E, Lawrence J, Jarolim P, toxic phase, occurs 1 to 4 months after Fischer GA, Larsen PR. Timing and magnitude of delivery when transient thyrotoxicosis increases in levothyroxine requirements during preg- nancy in women with hypothyroidism. N Engl J Med. develops from excessive release of thyroid 2004;351:241–249. hormones. The most common symptoms 6. American College of Obstetrics and Gynecology. with early postpartum thyroiditis are fa- ACOG Practice Bulletin. Clinical management guide- tigue and . Approximately lines for obstetrician-gynecologists. Number 37, August 2002. (Replaces Practice Bulletin Number 67% of these women will return to a 32, November 2001). Thyroid disease in pregnancy. euthyroid state, and thioamide therapy Obstet Gynecol. 2002;100:387–396. is generally considered ineffective. Hypo- 7. Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy thyroidism can develop within 1 month are associated with impaired psychomotor develop- of the onset of thyroiditis. ment in infancy. Clin Endocrinol. 1999;50:149–155. The second phase occurs between 8. Haddow JE, Palomaki GE, Allan WC, et al. Maternal 4 and 8 months postpartum, and these thyroid defi ciency during pregnancy and subsequent neuropsychological development of the child. N Engl women present with hypothyroidism. J Med. 1999;341:549–555. Thyromegaly and associated symptoms 9. Blazer S, Moreh-Waterman Y, Miller-Lotan R, Tamir are common. Unlike the fi rst (thyrotoxic) A, Hochberg Z. Maternal hypothyroidism may affect fetal growth and neonatal thyroid function. Obstet phase, medical treatment is recommend- Gynecol. 2003;102:232–241. ed. Thyroxine treatment should be initi- 10. Casey BM, Dashe JS, Wells CE, et al. Subclinical FAST TRACK ated and maintained for 6 to 12 months. hypothyroidism and pregnancy outcomes. Obstet Expect to see Postpartum thyroiditis carries a 30% risk Gynecol. 2005;105:239–245. 14 11. Klein RZ, Haddow JE, Faix JD, et al. Prevalence of a goiter in as of recurrence. thyroid defi ciency in pregnant women. Clin Endocri- Postpartum thyroiditis may be as- nol. 1991;35:41–46. many as half of sociated with depression or aggravate 12. Kooistra L, Crawford S, van Baar AL, Brouwers patients who have symptoms of depression, although the EP, Pop VJ. Neonatal effects of maternal hypo- thyroxinemia during early pregnancy. Pediatrics. postpartum data on this association are confl icting. 2006;117:161–167. hyperthyroiditis The largest study addressing this issue 13. Levothyroxine: Drug information. Lexicomp. concluded that there was no difference http://www.utdol.com/utd/content/topic. do?topicKey=drug_l_z/143814&type=A&selectedTitl in the clinical and psychiatric signs and e=2~39. Accessed December 14, 2007. symptoms between postpartum thyroid- 14. Casey BM, Leveno KJ. Thyroid disease in pregnancy. itis and controls.15 Nevertheless, it would Obstet Gynecol. 2006;108:1283–1292. seem prudent to evaluate thyroid function 15. Kent GN, Stuckey BG, Allen JR, Lambert T, Gee V. in if other signs of Postpartum thyroid dysfunction: clinical assessment and relationship to psychiatric affective morbidity. thyroid dysfunction are present. ■ Clin Endocrinol. 1999; 51:429–438.

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