Introduction

PREGNANCY HAS a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%–40% in areas of iodine deficiency. Production of thyroxine (T₄) and triiodothyronine (T₃) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. Sixteen percent of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception.

Knowledge regarding the interaction between the thyroid and pregnancy/the postpartum period is advancing at a rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted as the upper limit of normal for TSH in the first trimester. This has important implications in regards to interpretation of the literature as well as a critical impact for the clinical diagnosis of hypothyroidism. Although it is well accepted that overt hypothyroidism and overt hyperthyroidism have a deleterious impact on pregnancy, studies are now focusing on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and fetal health, the association between miscarriage and preterm delivery in euthyroid women positive for TPO and/or Tg antibody, and the prevalence and long-term impact of postpartum thyroiditis. Recently completed prospective randomized studies have begun to produce critically needed data on the impact of treating thyroid disease on the mother, fetus, and the future intellect of the unborn child.

It is in this context that the American Thyroid Association (ATA) charged a task force with developing clinical guidelines on the diagnosis and treatment of thyroid disease during pregnancy and the postpartum. The task force consisted of international experts in the field of thyroid disease and pregnancy, and included representatives from the ATA, Asia and Oceania Thyroid Association, Latin American Thyroid Society, American College of Obstetricians and Gynecologists, and the Midwives Alliance of North America. Inclusion of thyroidologists, obstetricians, and midwives on the task force was essential to ensuring widespread acceptance and adoption of the developed guidelines.

The clinical guidelines task force commenced its activities in late 2009. The guidelines are divided into the following nine areas: 1) thyroid function tests, 2) hypothyroidism, 3) thyrotoxicosis, 4) iodine, 5) thyroid antibodies and miscarriage/ preterm delivery, 6) thyroid nodules and cancer, 7) postpartum thyroiditis, 8) recommendations on screening for thyroid disease during pregnancy, and 9) areas for future research. Each section consists of a series of questions germane to the clinician, followed by a discussion of the questions and concluding with recommendations.

Literature review for each section included an analysis of all primary papers in the area published since 1990 and selective review of the primary literature published prior to 1990 that was seminal in the field. In the past 15 years there have been a number of recommendations and guideline statements relating to aspects of thyroid and pregnancy (1,2). In deriving the present guidelines the task force conducted a new and comprehensive analysis of the primary literature as the basis for all of the recommendations. The strength of each recommendation was graded according to the United States Preventive Services Task Force (USPSTF) Guidelines outlined below (3).

Level A. The USPSTF strongly recommends that clinicians provide (the service) to eligible patients. The USPSTF found good evidence that (the service) improves important health outcomes and concludes that benefits substantially outweigh harms.

Level B. The USPSTF recommends that clinicians provide (this service) to eligible patients. The USPSTF found at least fair evidence that (the service) improves important health outcomes and concludes that benefits outweigh harms.

Level C. The USPSTF makes no recommendation for or against routine provision of (the service). The USPSTF found at least fair evidence that (the service) can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation.

Level D. The USPSTF recommends against routinely providing (the service) to asymptomatic patients. The USPSTF found at least fair evidence that (the service) is ineffective or that harms outweigh benefits.

Level I. The USPSTF concludes that evidence is insufficient to recommend for or against routinely providing (the service). Evidence that (the service) is effective is lacking, or poor quality, or conflicting, and the balance of benefits and harms cannot be determined.

The organization of these guidelines is presented in Table 1. A complete list of the Recommendations is included in the Appendix. It should be noted that although there was unanimity in the vast majority of recommendations there were two recommendations for which one of the committee members did not agree with the final recommendation. The two recommendations for which there were dissenting opinions are Recommendations 9 and 76. The alternative view points are included in the body of the report.

The final document was approved by the ATA Board of Directors and officially endorsed by the American Association of Clinical Endocrinologists (AACE), British Thyroid Association (BTA), Endocrine Society of Australia (ESA), European Association of Nuclear Medicine (EANM), European Thyroid Association (ETA), Italian Association of Clinical Endocrinologists (AME), Korean Thyroid Association (KTA), and Latin American Thyroid Society (LATS).

Finally, the committee recognizes that knowledge on the interplay between the thyroid gland and pregnancy/postpartum is dynamic, and new data will continue to come forth at a rapid rate. It is understood that the present guidelines are applicable only until future data refine our understanding, define new areas of importance, and perhaps even refute some of our recommendations. In the interim, it is our hope that the present guidelines provide useful information to clinicians and help achieve our ultimate goal of the highest quality clinical care for pregnant women and their unborn children.

Table 1. Organization of Pregnancy Management Guidelines: Sections,
Questions, and Recommendations

Page number
INTRODUCTION
THYROID FUNCTION TESTS IN PREGNANCY
Q	1	How do thyroid function tests change during pregnancy?	1086
Q	2	What is the normal range for TSH in each trimester?	1086
R	1	Trimester-Specific Reference Ranges for TSH, # 1	1087
R	2	Trimester-Specific Reference Ranges for TSH, # 2	1087
Q	3	What is the optimal method to assess FT₄ during pregnancy?	1087
R	3	FT₄ Assay Methods, # 1	1088
R	4	FT₄ Assay Methods, # 2	1088
R	5	FT₄ Assay Methods, # 3	1088
HYPOTHYROIDISM IN PREGNANCY
Q	4	What are the definitions of OH and SCH in pregnancy?	1088
Q	5	How is isolated hypothyroxinemia defined in pregnancy ?	1088
Q	6	What adverse outcomes are associated with OH in pregnancy?	1088
Q	7	What adverse outcomes are associated with SCH in pregnancy?	1089
Q	8	What adverse outcomes are associated with isolated hypothyroxinemia in pregnancy?	1089
Q	9	Should OH be treated in pregnancy?	1090
R	6	Treatment of OH in Pregnancy	1090
Q	10	Should isolated hypothyroxinemia be treated in pregnancy?	1090
R	7	Isolated Hypothyroxinemia in Pregnancy	1090
Q	11	Should SCH be treated in pregnancy?	1090
R	8	Treatment of SCH in Pregnancy, # 1	1090
R	9	Treatment of SCH in Pregnancy, # 2	1090
Q	12	When provided, what is the optimal treatment of OH and SCH?	1090
R	10	The Optimal Form of Thyroid Hormone to Treat OH and SCH	1090
Q	13	When provided, what is the goal of OH and SCH treatment?	1090
R	11	Goal of LT₄ Treatment for OH and SCH	1090
Q	14	If pregnant women with SCH are not initially treated, how should they be monitored through gestation?	1090
R	12	Monitoring Women with SCH Who Are Not Initially Treated During Their Pregnancy	1090
Q	15	How do hypothyroid women (receiving LT₄) differ from other patients during pregnancy? What changes can be anticipated in such patients during gestation?	1091
Q	16	What proportion of treated hypothyroid women (receiving LT₄) require changes in their LT₄ dose during pregnancy?	1091
Q	17	In treated hypothyroid women (receiving LT₄) who are planning pregnancy, how should the LT₄ dose be adjusted?	1091
R	13	LT₄ Dose Adjustment for Hypothyroid Women Who Miss a Menstrual Period or Have a Positive Home Pregnancy Test	1091
Q	18	In hypothyroid women (receiving LT₄) who are newly pregnant, what factors influence thyroid status and LT₄ requirements during gestation?	1091
R	14	Factors Influencing Changes in LT₄ Requirements During Pregnancy	1091
R	15	Adjustment of LT₄ Dose in Hypothyroid Women Planning Pregnancy	1091
Q	19	In hypothyroid women (receiving LT₄) who are newly pregnant, how often should maternal thyroid function be monitored during gestation?	1091
R	16	Frequency that Maternal Serum TSH Should Be Monitored During Pregnancy in Hypothyroid Women Taking LT₄, # 1	1092
R	17	Frequency that Maternal Serum TSH Should Be Monitored During Pregnancy in Hypothyroid Women Taking LT₄, # 2	1092
Q	20	How should the LT₄ dose be adjusted postpartum?	1092
R	18	Dose Adjustment and Serum TSH Testing Postpartum	1092
Q	21	What is the outcome and long-term prognosis when SCH and OH are effectively treated through gestation?	1092
Q	22	Except for measurement of maternal thyroid function, should additional maternal or fetal testing occur in treated, hypothyroid women during pregnancy?	1092
R	19	Tests Other Than Serum TSH in Hypothyroid Women Receiving LT₄ Who Have an Uncomplicated Pregnancy	1092
Q	23	In euthyroid women who are TAb+ prior to conception, what is the risk of hypothyroidism once they become pregnant?	1092
Q	24	How should TAb+ euthyroid women be monitored and treated during pregnancy?	1092
R	20	Monitoring Women Without a History of Hypothyroidism, but Who Are TAb+ During Pregnancy	1092
Q	25	Should TAb+ euthyroid women be monitored or treated for complications other than the risk of hypothyroidism during pregnancy?	1092
R	21	Selenium Supplementation During Pregnancy for Women Who Are TPOAb+	1093
THYROTOXICOSIS IN PREGNANCY
Q	26	What are the causes of thyrotoxicosis in pregnancy?	1093
Q	27	What is the appropriate initial evaluation of a suppressed serum TSH concentration during the first trimester of pregnancy?	1093
Q	28	How can gestational hyperthyroidism be differentiated from Graves' hyperthyroidism in pregnancy?	1093
R	22	Workup of Suppressed Serum TSH in First Trimester of Pregnancy	1093
R	23	Ultrasound to Work-up Differential Diagnosis of Thyrotoxicosis in Pregnancy	1093
R	24	Prohibition of Radioactive Iodine Scans and Uptake Studies During Pregnancy	1093
Q	29	What is the appropriate management of gestational hyperthyroidism?	1093
R	25	Management of Women with Gestational Hyperthyroidism and Hyperemesis Gravidarum	1094
R	26	Antithyroid Drugs in the Management of Gestational Hyperthyroidism	1094
Q	30	How should women with Graves' disease be counseled before pregnancy?	1094
R	27	Need to Render Hyperthyroid Women Euthyroid Before Pregnancy	1094
Q	31	What is the management of patients with Graves' hyperthyroidism in pregnancy?	1094
R	28	Timing of PTU and MMI Use in Pregnancy	1094
R	29	Combining ATDs and LT₄ During Pregnancy	1094
Q	32	What tests should be performed in women treated during pregnancy with ATDs? What is the target value of FT₄?	1095
R	30	Monitoring Frequency of FT₄ and Target FT₄ in Women on Antithyroid Drugs During Pregnancy	1095
Q	33	What are the indications and timing for thyroidectomy in the management of Graves' disease during pregnancy	1095
R	31	Relative Role of Thyroidectomy and Its Timing for Managing Thyrotoxicosis in Pregnancy	1095
Q	34	What is the value of TRAb measurement in the evaluation of a pregnant women with Graves' hyperthyroidism?	1095
R	32	History of Graves' Disease as a Determinant of TRAb Measurement, and Timing of TRAb Measurement, in Pregnancy	1095
Q	35	Under what circumstances should additional fetal ultrasound monitoring for growth, heart rate, and goiter be performed in women with Graves' hyperthyroidism in pregnancy?	1095
R	33	Recommendations for Pregnant Women with High Risk of Fetal Thyroid Dysfunction	1096
Q	36	When should umbilical blood sampling be considered in women with Graves' disease in pregnancy?	1096
R	34	Cordocentesis in Pregnancy	1096
Q	37	What are the etiologies of thyrotoxicosis in the postpartum period?	1096
Q	38	How should the etiology of new thyrotoxicosis be determined in the postpartum period?	1096
Q	39	How should Graves' hyperthyroidism be treated in lactating women?	1096
R	35	Safe Doses of Antithyroid Drugs for Infants of Breastfeeding Mothers	1096
CLINICAL GUIDELINES FOR IODINE NUTRITION
Q	40	Why is increased iodine intake required in pregnancy and lactation, and how is iodine intake assessed?	1096
Q	41	What is the impact of severe iodine deficiency on the mother, fetus, and child?	1096
Q	42	What is the impact of mild to moderate iodine deficiency on the mother, fetus, and child?	1097
Q	43	What is the iodine status of pregnant and breastfeeding women in the United States?	1097
Q	44	What is the iodine status of pregnant and breastfeeding women worldwide?	1097
Q	45	Does iodine supplementation in pregnancy and lactation improve outcomes in severe iodine deficiency?	1097
Q	46	Does iodine supplementation in pregnancy and lactation improve outcomes in mildly to moderately iodine-deficient women?	1097
Q	47	What is the recommended daily iodine intake in women planning pregnancy, women who are pregnant, and women who are breastfeeding?	1097
R	36	Minimum Iodine Intake Requirements in Pregnant Women, # 1	1098
R	37	Minimum Iodine Intake Requirements in Pregnant Women, # 2	1098
R	38	Minimum Iodine Intake Requirements in Pregnant Women, # 3	1098
Q	48	What is the safe upper limit for iodine consumption in pregnant and breastfeeding women?	1098
R	39	Recommendation Against High Amounts of Iodine in Pregnancy, # 1	1098
R	40	Recommendation Against High Amounts of Iodine in Pregnancy, # 2	1098
SPONTANEOUS PREGNANCY LOSS, PRETERM DELIVERY, AND THYROID ANTIBODIES
Q	49	Is there an association between thyroid antibody positivity and sporadic spontaneous abortion in euthyroid women?	1099
Q	50	Should women be screened for TPO antibodies before or during pregnancy with the goal of treating TPOAb+ euthyroid women with LT₄ to decrease the rate of spontaneous miscarriage?	1099
R	41	Screening for Thyroid Antibodies in the First Trimester	1099
Q	51	Is there an association between thyroid antibodies and recurrent spontaneous abortion in euthyroid women?	1099
Q	52	Should women with recurrent abortion be screened for TAb before or during pregnancy with the goal of treating euthyroid TAb+ women with LT₄ or IVIG therapy to decrease the rate of recurrent spontaneous abortion?	1099
R	42	Screening for TAb+ and Treating TAb+ Women with LT₄ in the First Trimester	1099
Q	53	Should euthyroid women who are known to be TAb+ either before or during pregnancy be treated with LT₄ in order to decrease the chance of sporadic or recurrent miscarriage?	1100
R	43	Treating Euthyroid, TAb+ Women with LT₄ in Pregnancy	1100
Q	54	Is there an association between thyroid antibody positivity and pregnancy loss in euthyroid women undergoing IVF?	1100
Q	55	Should women undergoing in vitro fertilization be screened for TPOAb+ before or during pregnancy with the goal of treating euthyroid TPOAb+ women with LT₄ to decrease the rate of spontaneous miscarriage?	1100
R	44	Treating Euthyroid TAb+ Women Undergoing Assisted Reproduction Technologies with LT₄	1100
Q	56	Is there an association between thyroid antibodies and preterm delivery in euthyroid women?	1100
Q	57	Should women be screened for thyroid antibodies before or during pregnancy with the goal of treating TAb+ euthyroid women with LT₄ to decrease the rate of preterm delivery?	1100
R	45	First Trimester Screening for Thyroid Antibodies with Consideration of LT₄ Therapy to Decrease the Risk of Preterm Delivery	1100
THYROID NODULES AND THYROID CANCER
Q	58	What is the frequency of thyroid nodules during pregnancy?	1100
Q	59	What is the frequency of thyroid cancer in women with thyroid nodules discovered during pregnancy?	1101
Q	60	What is the optimal diagnostic strategy for thyroid nodules detected during pregnancy?	1101
R	46	Workup of Thyroid Nodules During Pregnancy	1101
R	47	Measurement of Serum Calcitonin in Pregnant Women with Thyroid Nodules	1101
R	48	Risk of FNA of Thyroid Nodules in Pregnancy	1102
R	49	FNA of Thyroid Nodules in Pregnancy	1102
R	50	Recommendation Against Use of Radioiodine in Pregnancy	1102
Q	61	Does pregnancy impact the prognosis of thyroid carcinoma?	1102
R	51	Time of Surgery for Pregnant Women with Well-Differentiated Thyroid Carcinoma	1102
R	52	Time of Surgery for Pregnant Women with Medullary Thyroid Carcinoma	1102
Q	62	What are the perioperative risks to mother and fetus of surgery for thyroid cancer during pregnancy?	1102
R	53	Risk of Surgery for Thyroid Carcinoma in the Second Trimester	1102
Q	63	How should benign thyroid nodules be managed during pregnancy?	1103
R	54	Surgery During Pregnancy for Benign Thyroid Nodules	1103
Q	64	How should DTC be managed during pregnancy?	1103
R	55	Role of Thyroid Ultrasound in Pregnant Women with Suspected Thyroid Carcinoma	1103
R	56	Time of Surgery for Pregnant Women with Differentiated Thyroid Carcinoma	1103
R	57	LT₄ Treatment in Pregnant Women with Differentiated Thyroid Carcinoma	1103
Q	65	How should suspicious thyroid nodules be managed during pregnancy?	1103
R	58	Time of Surgery for Pregnant Women with FNA Suspicious for Thyroid Cancer	1103
Q	66	What are the TSH goals during pregnancy for women with previously treated thyroid cancer and who are on LT₄ therapy?	1103
R	59	Goal for TSH Level in Pregnant Women with History of Thyroid Cancer	1104
Q	67	What is the effect of RAI treatment for DTC on subsequent pregnancies?	1104
R	60	Timing of Pregnancy in Women with a History of Radioactive Iodine Treatment	1105
Q	68	Does pregnancy increase the risk of DTC recurrence?	1105
Q	69	What type of monitoring should be performed during pregnancy in a patient who has already been treated for DTC prior to pregnancy?	1105
R	61	Role of Ultrasound and Tg Monitoring During Pregnancy in Women with a History of Low-Risk DTC	1105
R	62	Role of Ultrasound Monitoring in Women with DTC and High Thyroglobulin Levels or Persistent Structural Disease	1105
POSTPARTUM THYROIDITIS
Q	70	What is the definition of PPT and what are its clinical implications?	1105
Q	71	What is the etiology of PPT?	1105
Q	72	Are there predictors of PPT?	1105
Q	73	What is the prevalence of PPT?	1106
Q

Thyroid Cancer Guidelines from the American Thyroid Association

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Introduction