Clinical THYROIDOLOGY

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1 Clinical THYROIDOLOGY Editor-in Chief Jerome M. Hershman, MD Distinguished Professor of Medicine UCLA School of Medicine and VA Greater Los Angeles Healthcare System Endocrinology 111D, Wilshire Blvd. Los Angeles, CA Associate Editors: Albert G. Burger, MD Professor, University of Geneva, Geneva, Switzerland Edward G. Grant, MD Professor and Chairman of Radiology University of Southern California Los Angeles CA Angela M. Leung, MD, MSc Division of Endocrinology Health Sciences Assistant Clinical Professor UCLA David Geffen School of Medicine Jorge H. Mestman, MD Professor of Clinical Medicine and OB/GYN University of Southern California, Keck School of Medicine, Los Angeles, CA MD, Professor of Endocrinology, Claude-Bernard Lyon 1, University, Lyon, France Elizabeth N. Pearce, MD, MSc Associate Professor of Medicine, Boston University School of Medicine, Boston, MA Wendy Sacks, MD Cedars-Sinai Medical Center, Department of Medicine Health Sciences Assistant Clinical Professor University of California, Los Angeles Stephen W. Spaulding, MD Professor of Medicine, Department of Medicine University at Buffalo, SUNY Cord Sturgeon, MD Associate Professor of Surgery, Director of Endocrine Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL President Robert C. Smallridge, MD Secretary/Chief Operating Officer John C. Morris, III, MD Treasurer Gregory W. Randolph, MD. President-Elect Antonio Bianco, MD, PhD Past-President Hossein Gharib, MD Secretary-Elect Victor J. Bernet, MD Executive Director Barbara R. Smith, CAE Headquarters Office American Thyroid Association 6066 Leesburg Pike, Suite 550 Falls Church, VA Telephone: Fax: Web: Designed By Karen Durland Clinical Thyroidology Copyright American Thyroid Association, Inc. All rights reserved. VOLUME 27 ISSUE 7 JULY 2015 Clin Thyroidol 2015;27: Should Screening for Thyroid Peroxidase during Pregnancy Be Universal or Risk-Factor-Based? Aghajanian P, Spencer CA, Wilson ML, Lee RH, Goodwin TM, Mestman JH. Evaluation of risk-factor-based screening for thyroid peroxidase antibody positivity in pregnancy. Clin Endocrinol (Oxf). March 30, 2015 [Epub ahead of print]. SUMMARY Background The wide range of adverse outcomes of thyroid dysfunction and autoimmunity on pregnancy and the offspring (1-5) makes early and reliable detection of paramount importance; therefore, screening for thyroid dysfunction is recommended in pregnancy. However, it is not yet clear whether screening should be clinically oriented or universal. Targeted case finding for the presence of antithyroid peroxidase antibodies (TPOAb) in pregnancy has not yet been evaluated despite the high prevalence in the general female population (1, 6, 7). The aim of the study was to assess whether, in pregnant women, screening for TPOAb should be restricted to women considered at high risk for thyroid autoimmune disease or whether screening should be universal. Methods From April 2008 to December 2008, a total of 546 pregnant women (sample size defined based on the prevalence of TPOAb observed previously in the same institution), predominantly of Latina background, were recruited from two obstetrics clinics (Cedars-Sinai Medical Center and the Keck School of Medicine, USC, Los Angeles). Eligibility criteria were an age >18 years, singleton pregnancy, and gestational age 6 to 24 weeks. Age, race, gravidity, parity, prior pregnancy history, past medical history, smoking history, and history of medication use were recorded. The risk level for thyroid dysfunction was individually recorded by an interview run by a study investigator. High risk was defined as the presence of one or more of the following (8): personal or family history of thyroid disease, history of thyroid antibodies, history of goiter, symptoms/signs of thyroid dysfunction, personal history of type 1 169

2 diabetes mellitus or other autoimmune disorders, history of infertility, miscarriage, or preterm delivery, and history of head or neck irradiation. TPOAb (radioimmunoassay), serum TSH (reference values, 0.1 to 2.5 miu/l in the first trimester and 0.2 to 3.0 miu/l in the second) and FT 4 (reference values, 0.8 to 2.0 ng/dl) were measured in all women. Women with TPOAb levels 1 kiu/l were considered to have autoimmune thyroiditis. Overt hypothyroidism, subclinical hypothyroidism and isolated hypothyroxinemia were defined as usual. Subjects with positive TPOAb, but normal serum TSH and FT 4, were classified as having euthyroid thyroiditis. Patients with overt or subclinical hypothyroidism were referred to specialized endocrinology clinics. Results Screened at a median gestational age of 20 weeks, 311 (57%) of these 546 women were in the high-risk group and 235 (43%) in the low-risk group for thyroid dysfunction. The high-risk group was older, had a more advanced gestational age, was more gravid and more parous, and included more smokers. There were no differences between the high- and low-risk groups in TPOAb prevalence (10.9 vs. 7.2%) or mean (±SD) TPOAb levels (15.3±22.4 vs. 32.1±57.6 kiu/l), mean TSH levels (1.67±0.89 vs ±0.9 miu/l) or prevalence of elevated TSH (5.8 vs. 6.8%), but FT 4 levels were slightly higher in the high-risk group (0.94±0.14 vs. 0.91±0.13 ng/dl; P = 0.01). Sensitivity, specificity, positive predictive values, and negative predictive values of the case-finding method for identifying TPOAb positivity were 67, 44, 12, and 92%, respectively. On the whole, 54 of the 546 women were TPOAb-positive. In practical terms, 33% of the TPOAb-positive women were classified as low risk and, therefore, were missed by the risk-factor screening method. However, in logistic-regression analysis, risk factors such as a personal or a family history of thyroid disease were predictive of TPO positivity, while a history of miscarriage or preterm delivery was not significant. The significance of other risk factors (history of goiter, head or neck irradiation, type 1 diabetes, etc.) could not be evaluated as too uncommon in this study population. Maternal age, gravidity, and gestational age did not differ between TPO-negative and TPO-positive women. A history of smoking was more frequent in TPO-negative than in TPO-positive women. Mean TSH levels were higher in TPO-positive women (2.29±1.47 vs. 1.62±0.77 miu/l), while FT 4 values were not different (0.91±0.14 vs. 0.93±0.14 ng/dl), and prevalence of elevated TSH was higher in TPOAb-positive (17%) than in TPO-negative (5%) women. There was no difference in the prevalence of thyroid dysfunction in the TPO-positive (15 of 54 [28%]) and negative (98 of 492 [20%]) women, but overt hypothyroidism was more prevalent in the TPO-positive group (4 of 54 vs. 5 of 492, P = 0.007). However, the majority of the TPO-positive women had euthyroid thyroiditis. Subclinical hypothyroidism was detected in 5 of 54 TPO-positive and 20 of 492 TPO-negative women (P = 0.08) and isolated hypothyrotoxinemia in 6 of 54 and 73 of 492 in TPO-positive and TPO-negative women, respectively (P = 0.46). Conclusions The comparison of two approaches in evaluating the risk of thyroid dysfunction in pregnant women shows significant discrepancies. The case-finding method based on the recording of risk factors missed one third of the women who had TPOAb. However, while the positive predictive value of the case-finding method for identifying TPOAb positivity was low (12%), the negative predictive value was 92%. Notably, a family or a personal history of thyroid disease was predictive of TPO positivity. While the prevalence of thyroid dysfunction was not different in the TPO-negative and the TPO-positive women, mean TSH levels were higher and overt hypothyroidism more prevalent in the TPO-positive group. This work is in line with previous studies and confirms that there is not yet enough evidence in favor of universal screening of pregnant women for autoimmune thyroid disease. CLINICAL THYROIDOLOGY l MAY VOLUME 27 l ISSUE 5 l 2015

3 ANALYSIS AND COMMENTARY This prospective study of a large group of subjects yields important information on the approach for screening pregnant women for thyroid disorders. The risk-factor based screening for autoimmune disease would have missed 33% of pregnant women with TPOAb positivity. Personal and family histories of thyroid disease were the factors most strongly associated with the presence of TPOAb. Thyroid dysfunction was diagnosed in 28% of the TPOAb-positive subjects, a proportion not different from that in the TPO-negative subjects (20%), but there were more women with overt hypothyroidism in the TPO-positive group. The proportion of subclinical hypothyroidism was not different in TPO-positive (9%) and TPO-negative (4%) subjects. As to isolated hypothyroxinemia, its prevalence (11 to 15%) was similar in the two groups, in line with the fact that this condition is not associated with thyroid autoimmunity. The present study confirms the results of previous studies in that the case-finding based method fails to detect a large proportion of pregnant women with thyroid dysfunction. In a study by Vaidya et al. (9), the case-finding based approach would have missed one third of women with overt or subclinical hypothyroidism. In the prospective study by Horacek et al. (10), among the 49 screened women found to be positive on the basis of TSH, FT 4, and TPO determination, 27 (55%) had none of the 10 guideline risk factors. Moreover, in a well-defined subgroup of 42 women with autoimmune thyroiditis, 21 (50%) had no risk factors (10). In this study, the most promising risk factors included positive family history, history of miscarriage or preterm delivery and positive personal history (10). Another study confirms that case finding fails to detect thyroid disease in the majority of pregnant women (11). Thyroid autoimmune diseases, particularly hypothyroidism, have adverse effects on human pregnancy (12). Also, the presence of TPOAb, even in women who are biochemically euthyroid, is associated with adverse obstetric and neonatal outcomes such as miscarriage, preterm delivery, premature rupture of membranes, placental abruption, fetal death, postpartum thyroiditis, postpartum thyroid dysfunction, neonatal hyperbilirubinemia, sensorineural hearing loss, behavioral problems in children, and impaired development in the offspring (13, 14). The mechanism of this association remains unclear. Presence of TPOAb is indicative of autoimmune thyroiditis that might impair thyroid adaption to the increased functional demand related to pregnancy, leading to maternal hypothyroidism (15). Alternatively, TPOAb might be just a marker of an overactive immune/autoimmune status with adverse effects on the pregnancy unrelated to the thyroid. Only a few contradictory studies have been reported on the effect of levothyroxine treatment on obstetrical complications in pregnant women with euthyroid thyroiditis or subclinical hypothyroidism (16, 17). Universal screening of asymptomatic pregnant women for hypothyroidism in the first trimester is currently controversial. Most professional societies recommend case finding rather than universal screening. The American Thyroid Association recommends measurement of serum TSH in pregnant women if they are symptomatic, from an area of known moderate-to-severe iodine insufficiency, or have a family or personal history of thyroid disease, type 1 diabetes, miscarriage, preterm delivery, head and neck radiation, or morbid obesity (18). In the American Endocrine Society guidelines, some members recommended screening while others did not (19). The European Thyroid Association does not recommend universal screening because of lack of grade 1 evidence. However, the majority of the authors recommend universal screening because of the beneficial effects of levothyroxine treatment on unknown overt hypothyroidism and on obstetric outcome, and the fact that the targeted approach will miss a large percentage of women with subclinical hypothyroidism, especially in mildly iodine-deficient women (20). And a survey conducted in Maine showed that many practitioners have already implemented routine TSH testing in pregnant women (21). A European survey found similar results, with 42% of responders screening all pregnant women for thyroid CLINICAL THYROIDOLOGY l MAY VOLUME 27 l ISSUE 5 l 2015

4 dysfunction (22). In addition, in a recent study, universal screening of pregnant women in the first trimester for autoimmune thyroid disease was determined to be cost-effective, not only as compared with no screening but also as compared with screening of high-risk women (23). Clearly, a screening strategy for thyroid dysfunction and autoimmunity in women who are pregnant or planning to become pregnant is important and requires additional studies. References 1. Prummel MF, Wiersinga WM. Thyroid peroxidase autoantibodies in euthyroid subjects. Best Pract Res Clin Endocrinol Metab 2005;19: Glinoer D, Riahi M, Grün JP, et al. Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metab 1994;79: Negro R, Schwartz A, Gismondi R, et al. Thyroid antibody positivity in the first trimester of pregnancy is associated with negative pregnancy outcomes. J Clin Endocrinol Metab 2011;96: Epub March 16, Karakosta P, Alegakis D, Georgiou V, et al. Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab 2012;97:1-9. Epub September 26, Stagnaro-Green A, Schwartz A, Gismondi R, et al. High rate of persistent hypothyroidism in a largescale prospective study of postpartum thyroiditis in southern Italy. J Clin Endocrinol Metab 2011;96: Epub December 29, Lee RH, Spencer CA, Mestman JH, et al. Free T 4 immunoassays are flawed during pregnancy. Am J Obstet Gynecol 2008;200:260.e1-6. Epub December 27, Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T 4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87: Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92 (Suppl 8):S Vaidya B, Anthony S, Bilous M, et al. Detection of thyroid dysfunction in early pregnancy: universal screening or targeted high-risk case finding? J Clin Endocrinol Metab 2007;92: Epub October 10, Horacek J, Spitalnikova S, Dlabalova B, et al. Universal screening detects two-times more thyroid disorders in early pregnancy than targeted high-risk case finding. Eur J Endocrinol 2010;163: Epub August 3, Negro R, Schwartz A, Gismondi R, et al. Universal screening versus case finding for detection and treatment of thyroid hormonal dysfunction during pregnancy. J Clin Endocrinol Metab 2010;95: Epub June 9, Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341: Alexander EK. Autoimmunity: thyroid autoantibodies and pregnancy risk. Nat Rev Endocrinol 2011;7: Thangaratinam S, Tan A, Knox E, et al. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ 2011;342:d2616. CLINICAL THYROIDOLOGY l MAY VOLUME 27 l ISSUE 5 l 2015

5 15. Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 2003;9: Negro R, Formoso G, Manigieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 2006;91: Epub April 18, Debieve F, Duliere S, Bernard P, et al. To treat or not to treat euthyroid autoimmune disorder during pregnancy? Gynecol Obstet Invest 2009;67: Epub December 18, Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21: Epub July 25, De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97: Lazarus J, Brown RS, Daumerie C, et al European Thyroid Association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014;3: Epub June 7, Haddow JE, McClain MR, Palomaki GE, et al. Screening for thyroid disorders during pregnancy: results of a survey in Maine. Am J Obstet Gynecol 2006;194: Vaidya B, Hubalewska-Dydejczyk A, Laurberg P, et al. Treatment and screening of hypothyroidism in pregnancy: results of a European survey. Eur J Endocrinol 2012;166: Epub October 24, Dosiou C, Barnes J, Schwartz A, et al. Costeffectiveness of universal and risk-based screening for autoimmune thyroid disease in pregnant women. J Clin Endocrinol Metab 2012;97: Epub March 7, CLINICAL THYROIDOLOGY l MAY VOLUME 27 l ISSUE 5 l 2015