Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum
2011; Mary Ann Liebert, Inc.; Volume: 21; Issue: 10 Linguagem: Inglês
10.1089/thy.2011.0087
ISSN1557-9077
AutoresAlex Stagnaro‐Green, Marcos Abalovich, Erik K. Alexander, Fereidoun Azizi, Jorge H. Mestman, Roberto Negro, Angelita Nixon, Elizabeth N. Pearce, Offie P. Soldin, Scott Sullivan, Wilmar M. Wiersinga,
Tópico(s)Homicide, Infanticide, and Child Abuse
ResumoThyroidVol. 21, No. 10 Pregnancy and Fetal DevelopmentFree AccessGuidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and PostpartumThe American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum, Alex Stagnaro-Green, Marcos Abalovich, Erik Alexander, Fereidoun Azizi, Jorge Mestman, Roberto Negro, Angelita Nixon, Elizabeth N. Pearce, Offie P. Soldin, Scott Sullivan, and Wilmar WiersingaThe American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and PostpartumSearch for more papers by this author, Alex Stagnaro-GreenDepartments of Medicine and Obstetrics/Gynecology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.Search for more papers by this author, Marcos AbalovichEndocrinology Division, Durand Hospital, Favaloro University, Buenos Aires, Argentina.Search for more papers by this author, Erik AlexanderDivision of Endocrinology, Diabetes, and Hypertension, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts.Search for more papers by this author, Fereidoun AziziInternal Medicine and Endocrinology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medicine Sciences, Tehran, Iran.Search for more papers by this author, Jorge MestmanDepartment of Medicine and Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California.Search for more papers by this author, Roberto NegroDivision of Endocrinology, V. Fazzi Hospital, Lecce, Italy.Search for more papers by this author, Angelita NixonAngelita Nixon, CNM, LLC, Scott Depot, West Virginia.Search for more papers by this author, Elizabeth N. PearceSection of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts.Search for more papers by this author, Offie P. SoldinDepartments of Medicine, Oncology, and Obstetrics and Gynecology, Georgetown University Medical Center, Washington, District of Columbia.Search for more papers by this author, Scott SullivanDepartment of Obstetrics/Gynecology, Medical University of South Carolina, Charleston, South Carolina.Search for more papers by this author, and Wilmar WiersingaEndocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Search for more papers by this authorPublished Online:23 Sep 2011https://doi.org/10.1089/thy.2011.0087AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionPregnancy 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.Table 1. Organization of Pregnancy Management Guidelines: Sections, Questions, and Recommendations Page numberINTRODUCTIONTHYROID FUNCTION TESTS IN PREGNANCYQ1How do thyroid function tests change during pregnancy?1086Q2What is the normal range for TSH in each trimester?1086R1Trimester-Specific Reference Ranges for TSH, # 11087R2Trimester-Specific Reference Ranges for TSH, # 21087Q3What is the optimal method to assess FT4 during pregnancy?1087R3FT4 Assay Methods, # 11088R4FT4 Assay Methods, # 21088R5FT4 Assay Methods, # 31088HYPOTHYROIDISM IN PREGNANCYQ4What are the definitions of OH and SCH in pregnancy?1088Q5How is isolated hypothyroxinemia defined in pregnancy ?1088Q6What adverse outcomes are associated with OH in pregnancy?1088Q7What adverse outcomes are associated with SCH in pregnancy?1089Q8What adverse outcomes are associated with isolated hypothyroxinemia in pregnancy?1089Q9Should OH be treated in pregnancy?1090R6Treatment of OH in Pregnancy1090Q10Should isolated hypothyroxinemia be treated in pregnancy?1090R7Isolated Hypothyroxinemia in Pregnancy1090Q11Should SCH be treated in pregnancy?1090R8Treatment of SCH in Pregnancy, # 11090R9Treatment of SCH in Pregnancy, # 21090Q12When provided, what is the optimal treatment of OH and SCH?1090R10The Optimal Form of Thyroid Hormone to Treat OH and SCH1090Q13When provided, what is the goal of OH and SCH treatment?1090R11Goal of LT4 Treatment for OH and SCH1090Q14If pregnant women with SCH are not initially treated, how should they be monitored through gestation?1090R12Monitoring Women with SCH Who Are Not Initially Treated During Their Pregnancy1090Q15How do hypothyroid women (receiving LT4) differ from other patients during pregnancy? What changes can be anticipated in such patients during gestation?1091Q16What proportion of treated hypothyroid women (receiving LT4) require changes in their LT4 dose during pregnancy?1091Q17In treated hypothyroid women (receiving LT4) who are planning pregnancy, how should the LT4 dose be adjusted?1091R13LT4 Dose Adjustment for Hypothyroid Women Who Miss a Menstrual Period or Have a Positive Home Pregnancy Test1091Q18In hypothyroid women (receiving LT4) who are newly pregnant, what factors influence thyroid status and LT4 requirements during gestation?1091R14Factors Influencing Changes in LT4 Requirements During Pregnancy1091R15Adjustment of LT4 Dose in Hypothyroid Women Planning Pregnancy1091Q19In hypothyroid women (receiving LT4) who are newly pregnant, how often should maternal thyroid function be monitored during gestation?1091R16Frequency that Maternal Serum TSH Should Be Monitored During Pregnancy in Hypothyroid Women Taking LT4, # 11092R17Frequency that Maternal Serum TSH Should Be Monitored During Pregnancy in Hypothyroid Women Taking LT4, # 21092Q20How should the LT4 dose be adjusted postpartum?1092R18Dose Adjustment and Serum TSH Testing Postpartum1092Q21What is the outcome and long-term prognosis when SCH and OH are effectively treated through gestation?1092Q22Except for measurement of maternal thyroid function, should additional maternal or fetal testing occur in treated, hypothyroid women during pregnancy?1092R19Tests Other Than Serum TSH in Hypothyroid Women Receiving LT4 Who Have an Uncomplicated Pregnancy1092Q23In euthyroid women who are TAb+ prior to conception, what is the risk of hypothyroidism once they become pregnant?1092Q24How should TAb+ euthyroid women be monitored and treated during pregnancy?1092R20Monitoring Women Without a History of Hypothyroidism, but Who Are TAb+ During Pregnancy1092Q25Should TAb+ euthyroid women be monitored or treated for complications other than the risk of hypothyroidism during pregnancy?1092R21Selenium Supplementation During Pregnancy for Women Who Are TPOAb+1093THYROTOXICOSIS IN PREGNANCYQ26What are the causes of thyrotoxicosis in pregnancy?1093Q27What is the appropriate initial evaluation of a suppressed serum TSH concentration during the first trimester of pregnancy?1093Q28How can gestational hyperthyroidism be differentiated from Graves' hyperthyroidism in pregnancy?1093R22Workup of Suppressed Serum TSH in First Trimester of Pregnancy1093R23Ultrasound to Work-up Differential Diagnosis of Thyrotoxicosis in Pregnancy1093R24Prohibition of Radioactive Iodine Scans and Uptake Studies During Pregnancy1093Q29What is the appropriate management of gestational hyperthyroidism?1093R25Management of Women with Gestational Hyperthyroidism and Hyperemesis Gravidarum1094R26Antithyroid Drugs in the Management of Gestational Hyperthyroidism1094Q30How should women with Graves' disease be counseled before pregnancy?1094R27Need to Render Hyperthyroid Women Euthyroid Before Pregnancy1094Q31What is the management of patients with Graves' hyperthyroidism in pregnancy?1094R28Timing of PTU and MMI Use in Pregnancy1094R29Combining ATDs and LT4 During Pregnancy1094Q32What tests should be performed in women treated during pregnancy with ATDs? What is the target value of FT4?1095R30Monitoring Frequency of FT4 and Target FT4 in Women on Antithyroid Drugs During Pregnancy1095Q33What are the indications and timing for thyroidectomy in the management of Graves' disease during pregnancy1095R31Relative Role of Thyroidectomy and Its Timing for Managing Thyrotoxicosis in Pregnancy1095Q34What is the value of TRAb measurement in the evaluation of a pregnant women with Graves' hyperthyroidism?1095R32History of Graves' Disease as a Determinant of TRAb Measurement, and Timing of TRAb Measurement, in Pregnancy1095Q35Under what circumstances should additional fetal ultrasound monitoring for growth, heart rate, and goiter be performed in women with Graves' hyperthyroidism in pregnancy?1095R33Recommendations for Pregnant Women with High Risk of Fetal Thyroid Dysfunction1096Q36When should umbilical blood sampling be considered in women with Graves' disease in pregnancy?1096R34Cordocentesis in Pregnancy1096Q37What are the etiologies of thyrotoxicosis in the postpartum period?1096Q38How should the etiology of new thyrotoxicosis be determined in the postpartum period?1096Q39How should Graves' hyperthyroidism be treated in lactating women?1096R35Safe Doses of Antithyroid Drugs for Infants of Breastfeeding Mothers1096CLINICAL GUIDELINES FOR IODINE NUTRITIONQ40Why is increased iodine intake required in pregnancy and lactation, and how is iodine intake assessed?1096Q41What is the impact of severe iodine deficiency on the mother, fetus, and child?1096Q42What is the impact of mild to moderate iodine deficiency on the mother, fetus, and child?1097Q43What is the iodine status of pregnant and breastfeeding women in the United States?1097Q44What is the iodine status of pregnant and breastfeeding women worldwide?1097Q45Does iodine supplementation in pregnancy and lactation improve outcomes in severe iodine deficiency?1097Q46Does iodine supplementation in pregnancy and lactation improve outcomes in mildly to moderately iodine-deficient women?1097Q47What is the recommended daily iodine intake in women planning pregnancy, women who are pregnant, and women who are breastfeeding?1097R36Minimum Iodine Intake Requirements in Pregnant Women, # 11098R37Minimum Iodine Intake Requirements in Pregnant Women, # 21098R38Minimum Iodine Intake Requirements in Pregnant Women, # 31098Q48What is the safe upper limit for iodine consumption in pregnant and breastfeeding women?1098R39Recommendation Against High Amounts of Iodine in Pregnancy, # 11098R40Recommendation Against High Amounts of Iodine in Pregnancy, # 21098SPONTANEOUS PREGNANCY LOSS, PRETERM DELIVERY, AND THYROID ANTIBODIESQ49Is there an association between thyroid antibody positivity and sporadic spontaneous abortion in euthyroid women?1099Q50Should 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?1099R41Screening for Thyroid Antibodies in the First Trimester1099Q51Is there an association between thyroid antibodies and recurrent spontaneous abortion in euthyroid women?1099Q52Should 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?1099R42Screening for TAb+ and Treating TAb+ Women with LT4in the First Trimester1099Q53Should 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?1100R43Treating Euthyroid, TAb+ Women with LT4 in Pregnancy1100Q54Is there an association between thyroid antibody positivity and pregnancy loss in euthyroid women undergoing IVF?1100Q55Should 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?1100R44Treating Euthyroid TAb+ Women Undergoing Assisted Reproduction Technologies with LT41100Q56Is there an association between thyroid antibodies and preterm delivery in euthyroid women?1100Q57Should 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?1100R45First Trimester Screening for Thyroid Antibodies with Consideration of LT4 Therapy to Decrease the Risk of Preterm Delivery1100THYROID NODULES AND THYROID CANCERQ58What is the frequency of thyroid nodules during pregnancy?1100Q59What is the frequency of thyroid cancer in women with thyroid nodules discovered during pregnancy?1101Q60What is the optimal diagnostic strategy for thyroid nodules detected during pregnancy?1101R46Workup of Thyroid Nodules During Pregnancy1101R47Measurement of Serum Calcitonin in Pregnant Women with Thyroid Nodules1101R48Risk of FNA of Thyroid Nodules in Pregnancy1102R49FNA of Thyroid Nodules in Pregnancy1102R50Recommendation Against Use of Radioiodine in Pregnancy1102Q61Does pregnancy impact the prognosis of thyroid carcinoma?1102R51Time of Surgery for Pregnant Women with Well-Differentiated Thyroid Carcinoma1102R52Time of Surgery for Pregnant Women with Medullary Thyroid Carcinoma1102Q62What are the perioperative risks to mother and fetus of surgery for thyroid cancer during pregnancy?1102R53Risk of Surgery for Thyroid Carcinoma in the Second Trimester1102Q63How should benign thyroid nodules be managed during pregnancy?1103R54Surgery During Pregnancy for Benign Thyroid Nodules1103Q64How should DTC be managed during pregnancy?1103R55Role of Thyroid Ultrasound in Pregnant Women with Suspected Thyroid Carcinoma1103R56Time of Surgery for Pregnant Women with Differentiated Thyroid Carcinoma1103R57LT4Treatment in Pregnant Women with Differentiated Thyroid Carcinoma1103Q65How should suspicious thyroid nodules be managed during pregnancy?1103R58Time of Surgery for Pregnant Women with FNA Suspicious for Thyroid Cancer1103Q66What are the TSH goals during pregnancy for women with previously treated thyroid cancer and who are on LT4 therapy?1103R59Goal for TSH Level in Pregnant Women with History of Thyroid Cancer1104Q67What is the effect of RAI treatment for DTC on subsequent pregnancies?1104R60Timing of Pregnancy in Women with a History of Radioactive Iodine Treatment1105Q68Does pregnancy increase the risk of DTC recurrence?1105Q69What type of monitoring should be performed during pregnancy in a patient who has already been treated for DTC prior to pregnancy?1105R61Role of Ultrasound and Tg Monitoring During Pregnancy in Women with a History of Low-Risk DTC1105R62Role of Ultrasound Monitoring in Women with DTC and High Thyroglobulin Levels or Persistent Structural Disease1105POSTPARTUM THYROIDITISQ70What is the definition of PPT and what are its clinical implications?1105Q71What is the etiology of PPT?1105Q72Are there predictors of PPT?1105Q73What is the prevalence of PPT?1106Q74What symptoms are associated with PPT?1106Q75Is PPT associated with depression?1106R63Postpartum Depression as an Indication for Thyroid Function Testing1106Q76What is the treatment for the thyrotoxic phase of PPT?1106R64Propranolol Treatment of PPT1106R65Recommendation Against Use of ATDs to Treat PPT1106Q77Once the thyrotoxic phase of PPT resolves, how often should serum TSH be measured to screen for the hypothyroid phase1106R66Timing of Serum TSH After Resolution of the Thyrotoxic Phase of PPT, # 1 of 31106Q78What is the treatment for the hypothyroid phase of PPT?1106R67Timing of Serum TSH After PPT, # 2 of 31106R68Indication for Treatment with LT4 in Women with PPT1106Q79How long should LT4 be continued in women with postpartum thyroiditis?1106R69Indication and Method for Stopping LT4 in Women with a History of PPT1106Q80How often should screening be performed after the hypothyroid phase of PPT resolves?1107R70Timing of Serum TSH After PPT, # 3 of 31107Q81Does treatment of TAb+ euthyroid women with LT4 or iodine during pregnancy prevent PPT?1107R71Recommendation Against Use of LT4 or Iodine for Prevention of PPT in Euthyroid TAb+ Women1107Q82Does treatment of TAb+ euthyroid women with selenium during pregnancy prevent PPT?1107THYROID FUNCTION SCREENING IN PREGNANCYQ83Should all pregnant women be screened for serum TSH level in the first trimester of pregnancy?1107R72Recommendation Regarding Universal Screening with Serum TSH Determination at the First Trimester Visit1109R73Recommendation Regarding Universal Screening with Serum Free T4 Determination in Pregnant Women1109Q84Should serum TSH testing be carried out in a targeted population of pregnant women?1109R74Determination of Serum TSH Before Pregnancy in Women at High Risk for Hypothyroidism1110R75History Taking in Pregnant Women at Their Initial Prenatal Visit1110R76Determination of Serum TSH in Early Pregnancy in Women at High Risk for OH1111FUTURE RESEARCH DIRECTIONSATD, antithyroid drug; DTC, differentiated thyroid carcinoma; FNA, fine-needle aspiration; FT4, free thyroxine; IVF, in vitro fertilization; IVIG, intravenous immunoglobin; LT4, levothyroxine; MMI, methimazole; OH, overt hypothyroidism; PPT, postpartum thyroiditis; PTU, propylthiouracil; Q, Question; R, Recommendation; RAI, radioactive iodine; SCH, subclinical hypothyroidism; TAb+, positive for thyroid peroxidase antibody and/or thyroglobulin antibody; Tg, thyroglobulin; TPOAb+, positive for thyroid peroxidase antibody; TRAb, TSH receptor antibodies; TSH, thyrotropin.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.ResultsThyroid Function Tests in PregnancyQuestion 1: How do thyroid function tests change during pregnancy?To meet the challenge of increased metabolic needs during pregnancy, the thyroid adapts through changes in thyroid hormone economy and in the regulation of the hypothalamic-pituitary-thyroid axis (4,5). Consequently, thyroid function test results of healthy pregnant women differ from those of healthy nonpregnant women. This calls for pregnancy-specific and ideally trimester-specific reference intervals for all thyroid function tests but in particular for the most widely applied tests, TSH and free T4 (FT4).Following conception, circulating total T4 (TT4) and T4 binding globulin (TBG) concentrations increase by 6–8 weeks and remain high until delivery. Thyrotropic activity of hCG results in a decrease in serum TSH in the first trimester (5,6). Therefore, during pregnancy, women have lower serum TSH concentrations than before pregnancy, and frequently TSH is below the classical lower limit of 0.4 mIU/L (7,8).Most studies also report a substantial decrease in serum FT4 concentrations with progression of gestation (7,9,10). Serum FT4 measurements in pregnant women are complicated by increased TBG and decreased albumin concentrations that can cause immunoassays to be unreliable (11,12). Therefore the analytical method used for serum FT4 analysis should be taken into consideration.Question 2: What is the normal range for TSH in each trimester?There is strong evidence in the literature that the reference range for TSH is lower throughout pregnancy; i.e., both the lower normal limit and the upper normal limit of serum TSH are decreased by about 0.1–0.2 mIU/L and 1.0 mIU/L, respectively, compared with the customary TSH reference interval of 0.4–4.0 mIU/L of nonpregnant women. The largest decrease in serum TSH is observed during the first trimester and is transient, apparently related to hCG levels, which are highest early in gestation (Table 2). The median TSH values in the three trimesters in Table 2 are quite consistent, except for the study by Marwaha et al. (18) which, for unexplained reasons, reports higher TSH values throughout pregnancy. Serum TSH and its reference range gradually rise in the second and third trimesters, but it is noteworthy that the TSH reference interval remains lower than in nonpregnant women (13,15). Since hCG concentrations are higher in multiple pregnancies than in singleton pregnancies, the downward shift in the TSH reference interval is greater in twin pregnancies than in singleton pregnancies (19). In a study of 63 women with hCG concentrations >200,000 IU/L, TSH was suppressed (≤0.2 mIU/L) in 67% of women, and in 100% of women if hCG concentrations were >400,000 IU/L (20).Table 2. Sample Trimester-Specific Reference Intervals for Serum TSH TrimesteraReferenceFirstSecondThirdHaddow et al. (13)0.94 (0.08–2.73)1.29 (0.39–2.70)—Stricker et al. (14)1.04 (0.09–2.83)1.02 (0.20–2.79)1.14 (0.31–2.90)Panesar et al. (15)0.80 (0.03–2.30)1.10 (0.03–3.10)1.30 (0.13–3.50)Soldin et al. (16)0.98 (0.24–2.99)1.09 (0.46–2.95)1.20 (0.43–2.78)Bocos-Terraz et al. (17)0.92 (0.03–2.65)1.12 (0.12–2.64)1.29 (0.23–3.56)Marwaha et al. (18)2.10 (0.60–5.00)2.40 (0.43–5.78)2.10 (0.74–5.70)aMedian TSH in mIU/L, with parenthetical data indicating 5th and 95th percentiles (13,15,18) or 2.5th and 97.5th percentiles (14,16,17).In a small percentage of women, TSH can be very suppressed (<0.01 mIU/L) and yet still represent a normal pregnancy. There are slight but significant ethnic differences in serum TSH concentrations. Black and Asian women have TSH values that are on average 0.4 mIU/L lower than in white women; these differences persist during pregnancy (21,22). Pregnant women of Moroccan, Turkish, or Surinamese descent residing in The Netherlands, have TSH values 0.2–0.3 mIU/L lower than Dutch women throughout pregnancy (23). TSH ranges vary slightly depending on differences between methods of analysis (24). Subclinical hyperthyroidism is not associated with adverse pregnancy outcomes; therefore, a TSH value that is within detection is unlikely to be clinically significant (25).■ RECOMMENDATION 1Trimester-specific reference ranges for TSH, as defined in populations with optimal iodine intake, should be applied. Level B-USPSTF■ RECOMMENDATION 2If trimester-specific reference ranges for TSH are not available in the laboratory, the following reference ranges are recommended: first trimester, 0.1–2.5 mIU/L; second trimester, 0.2–3.0 mIU/L; third trimester, 0.3–3.0 mIU/L. Level I-USPSTFQuestion 3: What is the optimal method to assess FT4 during pregnancy?The normal ranges for FT4 index are calculated by TT4 × T3 uptake or a ratio of TT4 and TBG, but trimester-specific reference intervals for FT4 index have not been established in a reference population. Only 0.03% of serum TT4 content is unbound to serum proteins and is the FT4 available for tissue uptake. Sera TT4 concentrations are in the nanomolar range, but FT4 concentrations are in the picomolar range. Measuring FT4 in the presence of high concentrations of bound T4 has proved challenging especially in abnormal binding-protein states such as pregnancy.Equilibrium dialysis and ultrafiltration are used for physical separation of serum FT4 from bound T4 prior to analysis of the dialysate or ultrafiltrate. Assays based on classical equilibrium dialysis or ultrafiltration are laborious, time-consuming, expensive, and not widely available.FT4 immunoassay approaches are liable to error by disrupting the original equilibrium, which is dependent on dilution, temperature, buffer composition, affinity, and concentration of the T4
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