Thyroid and Pregnancy Fereidoun Azizi Research Institute for Endocrine Sciences

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. Elizabeth’s 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 Azizi’s 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 80’s 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 Center”and “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.

4. CONFLICT OF INTERESTSpeakers 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 FereidounAzizi Research Institute for Endocrine Sciences ShahidBeheshti 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.  E  TBG  TSH  FT4 • iodine TPO Ab  HCG  FT4  TSH  T4  TSH  placental DI III Factors for thyroid stimulation during pregnancy  goiter  Tg  TSH Delange: Int.J. Endocrinol. Metab. 2: 1, 2004

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, FereidounAzizi, Jorge Mestman, Roberto Negro, Angelina Nixon, Elizabeth N. Pearce, Office P. Soldin, Scott Sullivan and WilmarWiersinga 84 Questions 76 Recommendations Thyroid 2011; 21: 1081-1125

13. Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice GuidelineLeslie 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 SullivanJ ClinEndocrinolMetab, 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. 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 ate 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? • Obtain T4, resin T3 uptake and free T4 index • Measure free T4 by tandem mass spectrometry • Repeat free T4 measurement by a dependable lab • Measure serum Free T3

17. Physiologic changes in pregnancy that influence thyroid function tests Lazarus JH. Treat Endocrinol 2005; 4:31

18. 20 5.0 15 FT4(pmol/L) FT3(pmol/L) 4.0 10 0 0 1.5 50 40 1.0 TSH (mU/L) 30 hCG (I.Ux1000/L) 20 0.5 10 0 0 10 20 30 40 Postmenstrual age in weeks Glinoer, EndocrRev 1997;18:404-433

19. Sample trimester-specific reference intervals for TSH* Soldin OP et al. ClinChemActa 2004; 349: 181 Haddow JE et al. J Med Screen 2004; 11: 170 Panesar NS et al. Ann ClinBiocliem 2001; 34: 67

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

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

22. 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

23. Problems with FT4 in pregnancy • 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 Herbomes M et al. ClinChem Lab 2003; 41: 942 Roti E. J Endocrinol Invest 1991; 14: 1-9

24. Accurate Measurement of FT4 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 Yue et al. ClinChem 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 Free T4 index Trimester of pregnancy 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? • Obtain T4, resin T3 uptake and free T4 index • Measure free T4 by tandem mass spectrometry • Repeat free T4 measurement by a dependable lab • Measure serum Free T3

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? • Measure TPOAb • Increase levothyroxine to 175 g daily • Administer intraamnioticlevothyroxine • Continue current therapy

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 in1–2%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 Adopted from Stagnaro-Green A, J ClinEndocrinolMetabol 2009; 94: 21

32. NEUROPSYCHOLOGICAL TEST SCORES AMONG THE CHILDREN OF WOMEN WITH HYPOTHYROIDISM DURING PREGNANCY AS COMPARED WITHTHE CHILDREN OF MATCHED CONTROL WOMEN.* Haddow JE et al. N Engl J Med 1999; 341: 549

33. Guidelines for clinical management of maternal hypothyroidism during pregnancy • Check serum TSH level as soon as pregnancy is confirmed. • 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. • For previously diagnosed hypothyeoid women, monitor serum TSH every 3-4 weeks during first half of pregnancy and every 6 weeeks thereafter. • Adjust levothyroxine dosage to maintain serum TSH ( ≤ 2.5 mU/L 1st and ≤3.0, 2nd and 3rd) • Monitor serum TSH and total T4 levels 3-4 weeks after every dosage adjustment. When levothyroxine dosage achieves equilibrium, resume monitoring TSH alone. • 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. • After delivery, reduce levothyroxine to prepregnancy dosage, and check serum TSH in 6 weeks. LeBeau SO, Mandel SJ et al. EndocrinolMetabClin 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 levothyroxinedosing during pregnancy. Yassa L et al. J ClinEndocrinolMetab 2010; 95: 3234 Ablovich M. Thyroid 2010; 20: 1195

35. Hypothyroidism & Pregnancy • Recommendation 13Treated hypothyroid women on LT4 who are newly pregnant should increase T4 dose by 30% • Recommendation 15Treated hypothyroid women on LT4 who are planning pregnancy should have T4 dose adjusted to TSH <2.5 MIU/L • Recommendation 16Maternal serum TSH should be monitored every 4 weeks during 1st 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. ClinEndocrinol ,2012

37. HOW SHOULD LT4 BE ADJUSTED POSTPARTUM? Following delivery, LT4 should be reduced to the patient’s 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? • Measure TPOAb • Increase levothyroxine to 175 g daily • Administer intraamnioticlevothyroxine • Continue current therapy

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. • What are possible adverse outcomes in pregnancy? • What are possible fetal outcomes? • How do you manage this case?

40. 4,562 First trimester pregnant women 439 Hyper & TPOAb+ 4,123 TPOAb- 642 TSH 2.5-5.0 3,481 TSH <2.5 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

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 ClinEndocrinolMetab 2006; 91: 2587 Casey B et al. ObsetGynecol 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 ClinEndocrinolMetab 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. • What are possible adverse outcomes in pregnancy? • What are possible fetal outcomes? • How do you manage this case?

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 antithyroidperoxidase antibodies are strongly positive. Which one of the following is the next step in the management of this patients? • Assess for adrenal insufficiency before attempting pregnancy • Avoid pregnancy due to risk of recurrent miscarriage • Begin high-dose selenium suplementation • Follow patient and start levothyroxine after βHGG increase • Start levothyroxine and adjust to maintain a TSH value of 1-2 mIU/L

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

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

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