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Born in 1942, in Tehran, the capital city of Iran, Fereidoun Azizi obtained his MD from Tehran University, School of Medicine in 1966, Dr. Azizi then completed.

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Presentation on theme: "Born in 1942, in Tehran, the capital city of Iran, Fereidoun Azizi obtained his MD from Tehran University, School of Medicine in 1966, Dr. Azizi then completed."— Presentation transcript:

1 Born in 1942, in Tehran, the capital city of Iran, Fereidoun Azizi obtained his MD from Tehran University, School of Medicine in 1966, Dr. Azizi then completed his internal medicine speciality, endocrinology and methabolism subspeciality and nuclear medicine speciality from Tufts University, School of Medicine, Boston, USA and obtained three American Boards of Internal Medicine, Endocrinology and Metabolism, and Nuclear Medicine in 1972, 1973 and 1974, respectively. He was appointed assistant professor of medicine at Tufts University, and Chief of Endocrinology and acting-chief of Nuclear Medicine at St. Elizabeths Hospital of Boston, Tufts Medical School from 1974 until 1979, when he returned to Iran. He began his affilation with Beheshti University, and has since served as associate professor in 1979 and as professor of medicine and endocrinology since 1985. His appointements have been Dean of the medical school, Chancellor of Shahid Beheshti University of Medical Sciences, Head of the medical group of Supreme Council for Educational Programming and Director of Medical Commission of Council for Scientific Research in the Islamic Republic of Iran. He has served as President of Iranian College of Internal Medicine and is currently the president of the Iran Endocrine Society. Professor Azizi has been the Leading Professor and Director of Endocrine Division at Taleghani Medical center, Shahid Beheshti University of Medical Sciences since 1989 and Director of Endocrine Research Center since 1994. He has had a large endocrine practice since 1979. Professor Azizis many research contributions have been in various fields of endocrinology and metabolism, in particular the hypothalamic-pituitary-thyroid axis. He began his work with Professor L.E. Braverman in Boston and continued his interest in thyroid pathophysiology in Iran. He focused many of his research projects in 80s in iodine deficiency in Iran, presented the results to the Minister of Health of Iran in 1988 and initiated the first national IDD survey, which led to the formation of National Council for Control of Iodine Deficiency Disorders in Iran in 1989;

2 in order to ensure sustained elimination of iodine deficiency in the last 20 years in Iran. He also directed the national research project of Tehran Lipid and Glucose Study in the last 14 years. Professot Azizi was the Regional Coordinator for the Middle East and North Africa of Internaltional Council for Control of Iodine Deficiency Disorders (ICCIDD) and has served as consultant and advisor to WHO and UNICEF on multiple occasions. He is the Editor-in-Chief of the International Journal of Endocrinology and Metabolism. Professor Azizi has 1040 publications including 486 peer reviewed international paper and 524 scientific papers in Iranian medical Journals and 30 full text or chapters in scientific books. He is an invited reviewer for more than 26 scientific medical journals. He has received many awards including five awards from presidents of I.R. Iran for Distinguished Professor, Research Excellence, Kharazmi Feitival, Distinguished Research Centerand Health Promition in 1992, 1994, 1997, 2002 and 2008; State of Kwait Prize for excellence in diabetes in Eastern Mediterranean Region in 2007 and Nagataki Prize from Asia-Oceania Congress of Endocrinology in 2009. He was selected, as Distinguished Scienctist of the Year by Iranian Academy of Medical Sciences in 2011.

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4 CONFLICT OF INTEREST Speakers Name FEREIDOUN AZIZI ……………………………….. I have the following potential conflicts of interest to report: Research Contracts Consulting Employment in the Industry Stockholder of a healthcare company Owner of a healthcare company Other(s) I declare that I have no potential conflict of interest.

5 Thyroid and Pregnancy Fereidoun Azizi Research Institute for Endocrine Sciences Shahid Beheshti University of Medical Sciences Tehran, I.R. Iran Meet the professor 1

6 Objectives To review and discuss: Changes in thyroid economy during pregnancy Challenges with diagnosis of thyroid derangement in pregnancy Challenges with treatment of thyroid disease in pregnancy

7 Changes in Thyroid economy during pregnancy

8 goiter Tg TSH TBG E FT4 iodine TPO Ab TSH TSH placental DI III T4 TSH FT4 HCG Factors for thyroid stimulation during pregnancy Delange: Int.J. Endocrinol. Metab. 2: 1, 2004

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10 Iodine Requirement in Pregnancy ( g/day) During pregnancy Basal 150 40-50 % increased T4 requirements 50-100 transfer of T4 and I from mother to fetus 50 Increased renal clearance of I ? 250-300 Delange: Int.J. Endocrinol. Metab. 2: 1, 2004

11 Guidelines on thyroid and pregnancy The rapidly evolving data on the management of thyroid disorders during pregnancy have been the impetus for development of many guidelines during the past few years. It is noteworthy that two guidelines on thyroid and pregnancy were documented in October 2011 and August 2012 by American Thyroid Association and Endocrine Society, respectively.

12 Guideline of the American Thyroid Association for the diagnosis and Management of Thyroid Disease during Pregnancy and Postpartum The American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and postpartum Alex Stargnaro-Green (Chair), Marcos Abalovich, Erik Alexander, Fereidoun Azizi, Jorge Mestman, Roberto Negro, Angelina Nixon, Elizabeth N. Pearce, Office P. Soldin, Scott Sullivan and Wilmar Wiersinga 84 Questions 76 Recommendations Thyroid 2011; 21: 1081-1125

13 Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline Leslie De Groot, Marcos Abalovich, Erik K. Alexander, Nobuyuki Amino, Linda Barbour, Rhoda H. Cobin, Creswell J. Eastman, John H. Lazarus, Dominique Luton, Susan J. Mandel, Jorge Mestman, Joanne Rovet, and Scott Sullivan J Clin Endocrinol Metab, August 2012; 97 (8): 2543-2565

14 Challenges with diagnosis

15 A 25 year-old woman in the 8th week of pregnancy has serum TSH of 0.1 mU/L and serum free T4 of 2.5 and 1.4 ng/dl by two different laboratories. Pulse rate is 90/min, thyroid in not enlarged and there are no physical findings for Graves disease or hyperthyroidism.

16 Which one of the following would be your advise? a)Obtain T4, resin T3 uptake and free T4 index b)Measure free T4 by tandem mass spectrometry c)Repeat free T4 measurement by a dependable lab d)Measure serum Free T3 16

17 Physiologic changes in pregnancy that influence thyroid function tests Physiologic changeThyroid function test change Thyroid-binding globulin Serum total T4 and T3 First trimester hCG elevation Free T4 and TSH Plasma volume T4 and T3 pool size Type III 5-deiodinase (inner-ring deiodination) T4 and T3 degradation (resulting in requirement for increased hormone production) Thyroid enalrgement (in some women) Serum thyroglobulin Iodine clearance Hormone production in iodine- deficient areas hCG= human chorionic gonadotropin; TSH= Thyroid-stimulating hormone; T3= triiodothyronine; T4= thyroxine; = increased; =decreased Lazarus JH. Treat Endocrinol 2005; 4:31

18 Glinoer, Endocr Rev 1997;18:404-433

19 Sample trimester-specific reference intervals for TSH* Reference1st trimester2nd trimester3rd trimester Haddow0.94 (0.08-2.73)1.29 (0.39-2.70) Stricker1.04 (0.09-2.83)1.02 (0.20-2.79)1.14 (0.31-2.90) Panesar0.80 (0.03-2.30)1.10 (0.03-3.10)1.30 (0.13-3.50) Soldin0.98 (0.24-2.99)1.09 (0.46-2.95)1.20 (0.43-2.78) Bocos-Terraz0.92 (0.03-2.65)1.12 (0.12-2.64)1.29 (0.23-3.56) Marwaha2.10 (0.60-5.00)2.40 (0.43-5.78)2.10 (0.74-5.70) * median TSH mIU/L with 5th and 95th centiles or P2.5 and P 97.5 between brackets. Soldin OP et al. Clin Chem Acta 2004; 349: 181 Haddow JE et al. J Med Screen 2004; 11: 170 Panesar NS et al. Ann Clin Biocliem 2001; 34: 67

20 0.31 0.12 0.03 1.03 2.15 3.67 0.09 0.53 1.23 2.51 4.16 0.20 1.35 2.93 4.80 1 2 3 4 5 6 0 First trimester (n=7) Second trimester (n=5) Third trimester (n=2) Serum TSH (mU/l) TSH changes during pregnancy. The graph shows median values versus the range of 2.5 th and 97.5 th percentiles for each trimester of pregnancy Glinoer D, Spencer CA. Nat Rev Endocrinol 2010; 6: 526

21 Guidelines for Serum TSH During Pregnancy Recommendation 1 Trimester-specific reference ranges for TSH, as defined in populations with optimal iodine intake, should be applied Recommendation 2 If trimester-specific reference ranges for TSH are not available in the laboratory, the following references ranges are recommend: 1 st trimester, 0.1-2.5 mIU/L; 2 nd trimester, 0.2-3.0 mIU/L; 3 rd trimester, 0.3-3.0 mIU/L

22 Recommendations Topic American Thyroid Association (2011) Endocrine Society (2012) Thyroid function tests In the presence of a suppressed serum TSH in the first trimester (TSH <0.1 mIU/L), a history and physical examination are indicated. FT4 measurements should be obtained in all patients. Measurement of TT3 and TRAb may be helpful in establishing a diagnosis of hyperthyroidism. Same (R) Comparison of recommendations of American Thyroid Association and Endocrine Society on the management of hyperthyroidism before pregnancy and on the diagnosis of hyperthyroidism and pregnancy 22

23 High TBG concentrations result in higher FT4 values. Low albumin in serum will yield lower FT4 values. In pregnant women higher concentrations of TBG and NEFA and lower concentrations of albumin relative to sera of non-pregnant Seven commercial FT4 immunoassays in 23 euthyroid women at term: Albumin-dependent methods showed marked negative bias with up to 50% of subnormal values Other methods gave values above their non-pregnant reference values Problems with FT4 in pregnancy Herbomes M et al. Clin Chem Lab 2003; 41: 942 Roti E. J Endocrinol Invest 1991; 14: 1-9

24 The latest development in the field of FT4 analysis is to measure free thyroid hormones in the dialysate or ultrafiltrate using online solid phase extraction - liquid chromatography/tandem mass spectrometry. The 95% FT4 reference intervals decreased gradually with advancing gestational age: from 1.08-1.82 ng/dL in week 14 to 0.86-1.53 ng/dl in week 20 Accurate Measurement of FT4 Yue et al. Clin Chem 2008; 54: 642

25 WHAT IS THE OPTIMAL METHOD TO ASSESS FT4 DURING PREGNANCY? To measure FT4 in the presence of high concentrations of bound T4 has proved to be challenging especially in abnormal binding- protein states such as pregnancy. The normal ranges for FT4 index are calculated by TT4 x T3 uptake and TBG, but trimester-specific reference intervals for FT4 index have not been established.

26 Trimesters specific reference intervals for free T4 index in Iranian pregnant women Trimester of pregnancy Free T4 index Azizi F. et al. Thyroid, in press

27 A 25 year-old woman in the 8th week of pregnancy has serum TSH of 0.1 mU/L and serum free T4 of 2.5 and 1.4 ng/dl by two different laboratories. Pulser rate is 90/min, thyroid in not enlarged and there are no physical findings for Graves disease or hyperthyroidism. Which one of the following would be your advise? a)Obtain T4, resin T3 uptake and free T4 index b)Measure free T4 by tandem mass spectrometry c)Repeat free T4 measurement by a dependable lab d)Measure serum Free T3 27

28 A 25 year-old woman is in the 21st week of pregnancy. She gives a history of hypothyroidism for five years and is taking levothyroxine 150 g daily. Free T4 is 1.5 and serum TSH is 2.9 mU/L. Which one of the following would be your advise? a)Measure TPOAb b)Increase levothyroxine to 175 g daily c)Administer intraamniotic levothyroxine d)Continue current therapy 28

29 Hypothyroidism and pregnancy Overt hypothyroidism requiring thyroxine replacement is usually consequent to thyroid ablation for treatment of Graves disease, or to chronic autoimmune thyroiditis, and can be found in 1–2% of pregnant women, which means that it is more common than hyperthyroidism.

30 Hypothyroidism and pregnancy Untreated, inadequately treated and subclinical hypothyroidism are all associated with increased risk of miscarriage, pre-eclampsia, anaemia, fetal growth restriction, placental abruption, perinatal mortality and neonatal morbidity

31 Information on the nine studies that have evaluated the relationship between hypothyroidism and preterm delivery (PTD) and low birth weight First AtughotYearThyroid testPTDLow birth weight Jones1969BEIP<0.05 Montoro1981TSH Davis1988TSH Leung1993TSHP<0.02 Ablovich2002TSHNS Casey2005TSHP<0.05 Stagnaro-Green2005TSHNS Antolic2006HxNS Kibly2006TSHNSP<0.05 Adopted from Stagnaro-Green A, J Clin Endocrinol Metabol 2009; 94: 21

32 NEUROPSYCHOLOGICAL TEST SCORES AMONG THE CHILDREN OF WOMEN WITH HYPOTHYROIDISM DURING PREGNANCY AS COMPARED WITH THE CHILDREN OF MATCHED CONTROL WOMEN.* TEST CHILDREN OF WOMEN WITH HYPOTHYROIDIS M (N=62) CONTROL CHILDREN (N=124) MEAN DIFFERENCEP VALUE Intelligence WIS-III full-scale IQ score103 ±15107 ±12-4.1 ±2.10.06 WIS-III full-scale IQ score85 (%)1553 (1-8)0.08 Attention WIS-III freedom-from-distractribility score98 ±13102 ±13-3 ±20.08 Continuous Preformance Test score >8 (%) 37193 (1-3)0.01 Language World articulation10.1 ±2.510.2 ±2.4-0.2 ±0.40.80 World discrimination10.5 ±2.911.4 ±2.4-0.9 ±0.40.04 WIS-III verbal IQ score103±16107 ±16-4.2 ±2.20.06 A higher score or percentage indicates more problems. Haddow JE et al. N Engl J Med 1999; 341: 549

33 Guidelines for clinical management of maternal hypothyroidism during pregnancy 1. Check serum TSH level as soon as pregnancy is confirmed. 2. For newly diagnosed hypothyroid women, initial levothyroxine dosage is based on severity of hypothyroidism. For overt hypothyroidism, administer 2 µg/kg/d. If TSH is <10 mU/L, initial dose of 0.1 mg/d may be sufficient. 3. For previously diagnosed hypothyeoid women, monitor serum TSH every 3-4 weeks during first half of pregnancy and every 6 weeeks thereafter. 4. Adjust levothyroxine dosage to maintain serum TSH ( 2.5 mU/L 1st and 3.0, 2nd and 3rd) 5. Monitor serum TSH and total T4 levels 3-4 weeks after every dosage adjustment. When levothyroxine dosage achieves equilibrium, resume monitoring TSH alone. 6. Letothyroxine ingestion should be separated from prenatal vitamins containing iron, iron and calcium supplements, and soy products by at least 4 hours to ensure adequate absorption. 7. After delivery, reduce levothyroxine to prepregnancy dosage, and check serum TSH in 6 weeks. LeBeau SO, Mandel SJ et al. Endocrinol Metab Clin N AM 2006; 35: 117

34 WHAT PROPORTION OF TREATED HYPOTHYROID WOMEN (RECEIVING LEVOTHYROXINE) REQUIRE CHANGES IN THEIR LEVOTHYROXINE DOSE DURING PREGNANCY? The incremental increase depends, in part, on the etiology of the hypothyroidism. Dose increase will be required in those patients without functional thyroid tissue. Between 50 and 85% of treated hypothyroid women (receiving LT4) need to increase exogenous levothyroxine dosing during pregnancy. Yassa L et al. J Clin Endocrinol Metab 2010; 95: 3234 Ablovich M. Thyroid 2010; 20: 1195

35 Hypothyroidism & Pregnancy Recommendation 13 Treated hypothyroid women on LT4 who are newly pregnant should increase T4 dose by 30% Recommendation 15 Treated hypothyroid women on LT4 who are planning pregnancy should have T4 dose adjusted to TSH <2.5 MIU/L Recommendation 16 Maternal serum TSH should be monitored every 4 weeks during 1 st half of pregnancy Thyroid, 2011

36 Serum TSH concentrations in pregnant women by weeks of gestation * Median at pre-pregnancy The line indicates the median value at each gestational week Vadiveloo T, et al. Clin Endocrinol,2012

37 HOW SHOULD LT4 BE ADJUSTED POSTPARTUM? Following delivery, LT4 should be reduced to the patients preconception dose. Additional TSH testing should be performed 6 weeks postpartum.

38 A 25 year-old woman is in the 21st week of pregnancy. She gives a history of hypothyroidism for five years and is taking levothyroxine 150 g daily. Free T4 is 1.5 and serum TSH is 2.9 mU/L. Which one of the following would be your advise? a)Measure TPOAb b)Increase levothyroxine to 175 g daily c)Administer intraamniotic levothyroxine d)Continue current therapy 38

39 A 31 year-old woman in the 9th week of pregnancy has free T4 of 1.3 ng/dl and serum TSH of 8.0 mU/L. Physical examination is normal, TPOAb is negative. a)What are possible adverse outcomes in pregnancy? b)What are possible fetal outcomes? c)How do you manage this case? 39

40 3,481 TSH <2.5 642 TSH 2.5-5.0 Pregnancy loss 3.6% Pregnancy loss 6.1% P=0.006 Increased Pregnancy Loss in TPOAb-Neg Women with TSH 2.5-5.0 Negro R et al: JCEM 95:E44-8, 2010 439 Hyper & TPOAb+ 4,123 TPOAb- 4,562 First trimester pregnant women

41 WHAT ADVERSE OUTCOMES ARE ASSOCIATED WITH SUBCLINICAL HYPOTHYROIDISM IN PREGNANCY? Negro et al reported a significantly higher miscarriage rate in TPO Ab- women with TSH levels between 2.5-5 mIU/L compared to those with TSH levels below 2.5mIU/L (6.1% vs 3.6% respectively, p=0.006). 2-3 fold increased risk of pregnancy related complication was also confirmed in untreated women with SCH. No adverse effect from subclinical maternal hypothyroidism (detected in the 1st and 2nd trimester) in a cohort of 10,990 pregnant women. The majority of high-quality evidence suggests that SCH is associated with increased risk of adverse pregnancy outcomes. Negro R et al. J Clin Endocrinol Metab 2006; 91: 2587 Casey B et al. Obset Gynecol 2005; 105: 239

42 What Adverse Fetal Qutcomes Are Associated With Mothers Subclinical Hypothyroidism? The detrimental effect of SCH on fetal neurocognitive development is less clear. prospective, randomized study confirms no fetal IQ benefit from screening and treating subclinically hypothyroid women at 12 weeks of gestation. association between maternal SCH and adverse fetal neurocognitive development is biologically plausible, though not clearly demonstrated.

43 SHOULD SUBCLINICAL HYPOTHYROIDISM BE TREATED IN PREGNANCY? Potential increased risk of adverse outcome associated with subclinical hypothyroidism. Substantial absence of harmful effects associated with LT4 treatment. There is insufficient evidence to recommend for or against universal levothyroxine treatment in all pregnant women with SCH. Women with subclinical hypothyroidism in pregnancy who are not initially treated should be monitored for progression to overt hypothyroidism with a serum TSH approximately every 4 weeks until 16-20 weeks gestation. Middelton RSM et al. Cochrane Collaboration 2010; Issue 7 Negro R et al. J Clin Endocrinol Metab 2010; 95: E 44

44 Guidelines Recommendations Recommendation 8 There is insufficient evidence to recommend for or against universal LT4 Rx in TPOAB negative women with SCHypo Recommendation 9 Women who are positive for TPOAb and have SCHypo should be treated with LT4 Thyroid, 2011

45 A 31 year-old woman in the 9th week of pregnancy has free T4 of 1.3 ng/dl and serum TSH of 8.0 mU/L. Physical examination is normal. TPOAb is negative. a)What are possible adverse outcomes in pregnancy? b)What are possible fetal outcomes? c)How do you manage this case? 45

46 A 22 year-old woman with a family history of Hashimoto thyroiditis desires pregnancy. A prior pregnancy ended in spontaneous miscarriage at 6 weeks. On physical examination her pulse is 76 beats per minute, and her thyroid 25 gm without nodules. Serum TSH is 2.4 mIU/L, free T4 is normal, and antithyroid peroxidase antibodies are strongly positive. Which one of the following is the next step in the management of this patients? a)Assess for adrenal insufficiency before attempting pregnancy b)Avoid pregnancy due to risk of recurrent miscarriage c)Begin high-dose selenium suplementation d)Follow patient and start levothyroxine after βHGG increase e)Start levothyroxine and adjust to maintain a TSH value of 1-2 mIU/L 46

47 Thyroid Autoimmunity and pregnancy In 1990 a study reported that euthyroid women who were thyroid antibody positive in the first trimester of pregnancy have a miscarriage rate that is twice as high as women who are euthyroid and thyroid antibody negative. Muliple studies have confirmed this relationship and explored the impact of thyroid antibody positivity in women with recurrent abortion and women who achieved pregnancy through in vitro fertilizaytion. To date, five studies have evaluated the impact of therapeutic interventions in euthyroid antibody possitive women.

48 Thyroid Antibodies and Spontaneous Miscarriage Ab + Ab – Stagnaro-Green (1990) Glinoer (1991) Lejeune (1993) Singh (1995) Lijima (1997) Bagis (2001) Netto (2004) Glafoor (2006) Negro (2006)

49 Recurrent Abortion and Thyroid Antibodies Ab + Ab – Pratt (1993) Bassen (1995) Bassen (1997) Esplin (1998) Kutteh (1999) Dendrinos (2000)

50 Forest plot showing the association between TPO- Ab and risk of preterm delivery He X et al. Eur J Endocrinol 2012;167:455-464

51 IN EUTHYROID WOMEN WHO ARE TPOAB+ PRECONCEPTION, WHAT IS THE RISK OF HYPOTHYROIDISM ONCE PREGNANT?

52 Treatment with LT4 in Pregnant Women with TAI: Effects on Obstetrical Complications OUTCOMEOUTCOME Negro R et al: JCEM 91:2587-2591, 2006 58 TPOAb + No treatment 57 TPOAb + LT4 869 TPOAb- LT4: 0.5 g/kg.d TSH <1.0 mIU/I 0.75 g/kg.d TSH 1.0-2.0 mIU/I 1 g/kg.d for TSH >2.0 mIU/I or TPOAb >1,500 kIU/L 115 TPOAb + 984 pregnant women

53 TSH concentration during gestation in 3 study groups Negro R. J Clin Endocrinol Metab 2006; 91: 2587 Free T4 concentration during gestation in 3 study group Treatment with LT4 in Pregnant Women with TAI: Effects on Obstetrical Complications

54 Negro R et al: JCEM 91:2587-2591, 2006 % MiscarriagePreterm Delivery

55 SHOULD EUTHYROID WOMEN WHO ARE KNOWN TO BE THYROID ANTIBODY POSITIVE EITHER BEFORE OR DURING PREGNANCY BE TREATED WITH LEVOTHYROXINE IN ORDER TO DECREASE THE CHANCE OF SPORADIC OR RECURRENT MISCARRIAGE? There is insufficient evidence to recommend for or against treating with levothyroxine for thyroid antibodies in euthyroid women with sporadic or recurrent miscarriage before or during pregnancy.

56 A 22 year-old woman with a family history of Hashimoto thyroiditis desires pregnancy. A prior pregnancy ended in spontaneous miscarriage at 6 weeks. On physical examination her pulse is 76 beats per minute, and her thyroid 25 gm without nodules. Serum TSH is 2.4 mIU/L, free T4 is normal, and antithyroid peroxidase antibodies are strongly positive. Which one of the following is the next step in the management of this patients? a)Assess for adrenal insufficiency before attempting pregnancy b)Avoid pregnancy due to risk of recurrent miscarriage c)Begin high-dose selenium suplementation d)Follow patient and start levothyroxine after βHGG increase e)Start levothyroxine and adjust to maintain a TSH value of 1-2 mIU/L 56

57 A 30 year-old woman seeks pre-conception thyroid counseling. There is no personal or familial history of thyroid disease. She has a palpable thyroid of aprox. 20 gm in weight and is euthyroid. Which one of the following would be your advise before pregnancy? a)Thyroid screening is not indicated b)Measure serum TSH c)Assess TPOAb d)Measure both TSH and TPOAb 57

58 Relative Risks for raised and fully suppressed TSH at universal screening in UK (n=1560) Risk factorsRaised TSH (4.2 mIU/liter) RR95% CIP value Personal history of thyroid disease 12.26.8-22<0.0001 Personal history of type 1 diabetes and other Autoimmune disorders 4.81.3-18.20.016 Family history of thyroid disorders 3.41.8-6.2<0.0001 TPOAbs8.44.6-15.3<0.0001 Older age (35 yr)1.40.7-2.80.551 Smoking (all smokers)1.00.8-1.20.993 Smoking during pregnancy 0.40.25-0.60.03 Previous pregnancy0.90.7-1.10.739 History of miscarriage1.31.1-1.60.425 Vaidya B et al. J Clin Endocrinol Metab 2007; 92: 203

59 High-risk patients in which screening for thyroid disorders is indicated History of infertility, Menstrual irregularity Family history of thyroid disorders History of other autoimmune diseases History of goiter or features suggestive of hyperthyroidism Recurrent miscarriage or later pregnancy loss Recurrent obstetric complications that include placental abruption, Previous children with impaired neuo-psychointellectual development Insufficient dietary intake of iodine-containing food Other evidences Targeted screening of only the high-risk group misses 30-85% of hypothyroidism Vaidya B et al. J Clin Endocrinol Metab 2007; 92: 203 Horacek J et al. Europ J Endocrinol 2010; 163: 650 Wang W. Europ J Endocrinol 2010; 164: 263 Screening all pregnant women for autoimmune thyroid disease is cost effective Dosiou C et al. Europ J Endocrinol 2008; 158: 841

60 Comparison of the prevalence of thyroid disorders in the high-risk group and the non-high risk group. Wang W, Euro J Endocrinol 2010; 164: 263

61 The rates of missed diagnoses if screening were to be performed only in the high-risk population Wang W, Euro J Endocrinol 2010; 164: 263

62 Criteria for Screening 1. The condition sought should be an important health problem 2. Facilities should be available for confirmation of the diagnosis 3. There is an effective treatment 4. Early detection and treatment reduces morbidity and mortality 5. The expected benefits of early detection exceed the risks and costs. 6. There is a test that can detect the disease prior to the onset of signs and symptoms The test must satisfy the criteria of: Acceptability, Repeatability, Validity, Simplicity, Safety, Rapidity ease of administration, cost.

63 Antenatal thyroid screening and childhood cognitive function John H. Lazarus, M.D., Jonathan P. Bestwick, M.Sc., Sue Channon, D.Clin.Psych., Ruth Paradice, Ph.D., Aldo Maina, M.D., Rhian Rees, M.Sc., Elisabetta Chiusano, M.Psy., Rhys John, Ph.D., Varvara Guaraldo, M.S.Chem., Lynne M. George, H.N.C., Marco Perona, M.S.Chem., Daniela Dall'Amico, M.D., Arthur B. Parkes, Ph.D., Mohammed Joomun, M.Sc., and Nicholas J. Wald, F.R.S. N Engl J Med 2012; 366:493-501

64 Lazarus et al: N Engl J Med 2012;366:493-501 21,846 pregnant women at 11-14 weeks ScreenControl TSH >97.5 th % FT4 <2.5 th % T4Rx Follow IQ test in all children at age 3 were similar

65 Standardized Full-Scale Child IQ and Scores on the Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function, Preschool Version (Brief-P), According to Study Group* TestScreening Group (N = 390 Control Group (N = 404) Difference (95% CI) (Control Group Screening Group) P Value IQ Mean 99.2±13.3100.0±13.30.8 (1.1 to 2.6) 0.40 <85 (% of children) 12.1 14.1 2.1 (2.6 to 6.7) 0.39 CBCL T score Mean 44.4±12.4 45.1±13.60.7 (1.2 to 2.5) 0.49 Brief-P T score§ Median40 00.59 Interquartile range 47–55 47-55 * Plus–minus values are means ±SD. The full-scale child IQ test was standardized so that for each psychologist, the mean score among the children in the control group whom they tested was 100. In the screening group, the women were assigned to treatment with levothyroxine. For percentages of children with an IQ below 85, the absolute (percentage-point) differences are shown. For the CBCL, a T score above the 98th percentile is indicative of a clinically significant problem. § For the Brief-P, a T score above 65 is indicative of a clinically significant problem. N Engl J Med 2012; 366:493-501

66 Screening for Thyroid Disease in Pregnancy Although the benefits of universal screening for thyroid dysfunction may not be justified at this time, selected screening for the following should be done: Positive FHx thyroid disease Goiter TPOAb+ Symptoms Type 1 DM Miscarriage Other autoimmune disease Infertility Morbid obesity >30 years Thyroid 2011

67 A 30 year-old woman seeks pre-conception thyroid counseling. There is no personal or familial history of thyroid disease. She has a palpable thyroid of aprox. 20 gm in weight and is euthyroid. Which one of the following would be your advise before pregnancy? a)Thyroid screening is not indicated b)Measure serum TSH c)Assess TPOAb d)Measure both TSH and TPOAb 67

68 A 28 year-old woman is referred for pre- pregnancy counseling. She has Graves disease for 10 months and is currently taking 5 mg of methimazole daily. Serum free T4 is 1.3 ng/dl and TSH is 1.2 mU/L. 68

69 A 28 year-old woman is referred for pre-pregnancy counseling. She has Graves disease for 10 months and is currently taking 5 mg of methimazole daily. Serum free T4 is 1.3 ng/dl and TSH is 1.2 mU/L. Which one of the following would be your advise before pregnancy? a)Radioiodine treatment and avoidance of pregnancy for 6 months b)Subtotal thyroidectomy and attempt pregnancy after euthyroidism achieved c)Change to 50 mg propylthiouracil, check TFTs before attemping conception d)Continue current therapy 69

70 HOW SHOULD WOMEN WITH GRAVES DISEASE BE COUNSELED PRE-PREGNANCY? Hyperthyroidism should be well controlled before attempting pregnancy. Patients on anti-thyroid drugs should be switched to PTU when pregnancy is being attempted or at time of conception (?). In patients with high titers of TRAb antibodies requiring definitive therapy for Graves disease in the setting of a planned pregnancy within the next two years, surgery is preferable to radioactive iodine (?).

71 0 10 20 30 40 50 60 70 0 1 2 3 4 5 Years Radioiodine Surgery Medication TSH receptor autoimmunity in Graves disease after therapy TRAb % Laurberg et al EJE 2008

72 A 28 year-old woman is referred for pre-pregnancy counseling. She has Graves disease for 10 months and is currently taking 5 mg of methimazole daily. Serum free T4 is 1.3 ng/dl and TSH is 1.2 mU/L. Which one of the following would be your advise before pregnancy? a)Radioiodine treatment and avoidance of pregnancy for 6 months b)Subtotal thyroidectomy and attempt pregnancy after euthyroidism achieved c)Change to 50 mg propylthiouracil, check TFTs before attemping conception d)Continue current therapy 72

73 A 23 year-old woman in the second trimester of pregnancy is taking 5 mg methimazole for treatment of Graves disease. She notes occasional palpitations and difficulty sleeping. Her pulse rate is 90 beats per minute. Current thyroid function testing shows a serum TSH of 0.1 mIU/L and free T4 of 1.5 ng/dl (normal second-trimester range, 0.8-1.5 ng/dl). Which one of the following would you advise at this time? a) Change methimazole to propulthiouracilb) Increase methimazole c) Refer for thyroidectomye) Continue current therpay 73

74 Spencer CA 2006 Stimulate Mother T3 Fetus TPOAb & TgAb TSH receptor antibodies TRH TSH Block T3 T4 Placenta Anti-thyroid drugs

75 Management of thyrotoxicosis in pregnancy Confirm diagnosis Start propylthiouracil or methimazole Render patient euthyroid: continue with low-dose ATD up to and during labor and postpartum Monitor thyroid function: Throughout gestation; adjust ATD if necessary to maintain T4 at upper level of normal Check TSAb at 26 weeks Discuss treatment with patient effect on patient effect on fetus breast feeding Inform obstetrician and pediatrician Review postpartum-check

76 Comparison of recommendations of American Thyroid Association and Endocrine Society on the treatment of hyperthyroidism in pregnancy Topic Recommendations American Thyroid Association (2011) Endocrine Society (2012) Antithyroid (ATD) treatment PTU is preferred for the treatment of hyperthyroidism in the first trimester, patients on MMI should be switched to PTU if pregnancy is confirmed in the first trimester. Following the first trimester, consideration should be given to switching to MMI Propylthiouracil (PTU), if available, is recommended as the first-line drug for treatment of hyperthyroidism during the first trimester of pregnancy because of the possible association of methimazole (MMI) with specific congenital abnormalities that occur during first trimester organogenesis, MMI may also be prescribed if PTU is not available or if a patient cannot tolerate or has an adverse response to PTU. Practitioners should use their clinical judgment in choosing the ATD therapy, including the potential difficulties involved in switching patients from one drug to another, If switching from PTU to MMI, thyroid function should be assessed after 2 wk and then at 2-to 4-wk intervals.

77 Serum TSH determination in early gestation BelowAboveWithin First trimester reference range Measure FT4I or free T4No further action T4 status elevated measure TR-Ab TPO-Ab usually positive T4 status normal ( or moderately elevated) TPO-Ab usually negative Overt thyrotoxicosis ( probable cause: gestational transient thyrotoxicosis) Antithyroid drugs Monitor TR- Ab ( for risk of fetal hyperthyroidism) Subclinical thyrotoxicosis ( probable cause: gestational transient thyrotoxicosis) No treatment needed in most cases T4 status subnormal TPO-Ab positive or negative Overt hypothyroidism T4 status normal TPO-Ab positiveTPO-Ab negative Subclinical hypothyroidism Iolated hypo- T4 Levothyotoxine Algorithm for the detection of thyroid dysfunction in pregnancy based on initial serum TSH determination Hyperthyroidism Hypothyroidism Glinoer D, Spencer CA. Nat Rev Endocrinol 2010; 6: 526

78 A 24 year-old woman develops thyrotoxicosis three months following an uncomplicated pregnancy. She is breastfeeding. On physical exam, pulse is 104 beats per minute and the thyroid is 30 grams and non-tender. Free T4 is 2.3 (0.8-1.8 ng/dl); TSH is 0.01 mIU/L. Thyroid stimulating immunoglobulins are 125% (normal <125%). Which of the following tests should be done to establish the correct diagnosis? a)Anti-TPO antibodies b)Serum thyroglobulin level c)Thyroid ultrasound with Doppler flow d)131I Radioactive iodine uptake e)Thyroid fine-needle aspiration 78

79 HOW SHOULD GRAVES HYPERTHYROIDISM BE TREATED IN LACTATING WOMEN? Methimazole in doses up to 20-30 mg daily is safe for lactating mothers and their infants. PTU is a second-line agent due to concerns about severe hepatotoxicity, but is safe for lactating mothers and their infants in doses up to 300 mg daily. Azizi F et al J Endocrinol Invest 2006; 29:244 Azizi F et al. J Ped Endocrinol Metab 2003; 16: 1239 Azizi F et al. J Clin Endocrinol Metab 2000; 85: 3233

80 A comparison of recommendations of the American Thyroid Association (2011) and the Endocrine Society (2012) on various aspects of diagnosis and treatment of hyperthyroidism in pregnancy does not reveal any disagreement or controversy. Almost all the information given by one organization could be found in the text or recommendations of the other. Comparison of ATD and ES guidelines 80

81 The presence of two guidelines in a time distance of only 10 months by 2 prestigious organizations may perplex clinicians to select one guideline or the other for management of their patients. In my opinion any of the two guidelines may be used for appropriate and up-to- date management of thyroid disorders in pregnant women. Conclusion 81

82 Conclusion Thyroid diseases, both clinical and subclinical, are common during pregnancy and postpartum and influence the health of mother, fetus and infant. Effective evidence based strategies for both detection and management should be developed for the benefit of both mother and child. Prompt and appropriate treatment of thyroid disease could dramatically improve the pregnancy outcome and ensure health promotion for mother and infant.

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84 Recommendations for the Treatment of Graves Hyperthyroidism in Pregnancy Start US monitoring of the fetus from gestational week 22 Fetal goiter (vascular pattern) Fetal tachycardia: Delayed bone maturation: Advanced bone maturity Fetal movements Measure TSH-R Ab in the mother serum at 22-24 gestational weeks Check thyroid function in the neonate (cord blood, 1st and 2nd week of life) Search for TSH-R Ab in the neonate serum (if positive in the mother) Check maternal thyroid function in the post-partum

85 Summary of Recommendations No recommendation for universal screening in the first trimester of pregnancy. No recommendation to use free T4 as screening tool. Recommendation for verbal screening of all pregnant women at the first prenatal visit, for history of thyroid disease and thyroid medication. Recommendation to define high risk pregnant women based on 1. Symptoms or positive history for thyroid disease/surgery 2. TPOAb-positivity 3. Autoimmune diseases 4. Past head and neck radiation 5. Family history of thyroid diseases 6. Use of specific drugs. Recommendation to screen pregnant women at high risk for thyroid dysfunction by determining TSH level in serum: 1. In the first trimester of pregnancy 2. Using trimester specific TSH levels

86 Randomization and Follow-up of the Study Participants N Engl J Med 2012; 366:493-501


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