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Thyroid Disease & Pregnancy

2 nd International Endocrine Congress Esfahan, Iran October 10-12, 2012. Thyroid Disease & Pregnancy. Hossein Gharib, MD, MACP, MACE Professor of Medicine, Mayo Clinic College of Medicine President-Elect, American Thyroid Association. Disclosure & Thanks. Nothing to disclose

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Thyroid Disease & Pregnancy

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  1. 2nd International Endocrine Congress Esfahan, IranOctober 10-12, 2012 Thyroid Disease & Pregnancy Hossein Gharib, MD, MACP, MACEProfessor of Medicine, Mayo Clinic College of MedicinePresident-Elect, American Thyroid Association

  2. Disclosure & Thanks • Nothing to disclose • My sincere thanks for the invitation to be with you today • This presentation is based on clinical evidence, recent guidelines and good clinical judgment

  3. Thyroid & Pregnancy Physiologic changes •  TBG •  I requirement •  urinary I excretion •  T4 & T3 synthesis •  HCG •  immunity

  4.  E  TBG  TSH  FT4 • iodine TPO Ab  HCG  FT4  TSH  T4  TSH  placental DI III Changes in maternalThyroid Function in Pregnancy  goiter  Tg  TSH Modified from JCEM 86:2349, 2001

  5. Presentation of Thyroid Disease in General • Goiter • Symptoms of hyper- or hypothyroidism This is also the case in autoimmunethyroid diseases and also the caseduring pregnancy

  6. Hypothyroidism and Pregnancy • Hypothyroidism occurs in 0.05% of all pregnancies • SCHypo occurs in 2.5-5% • Symptoms are masked and diagnosis often overlooked • Most common cause worldwide is I deficiency; in U.S. Hashimoto thyroiditis Endo metab Clin N Am 31:893, 2004

  7. Screening for Thyroid Disease in Pregnancy A 24-year-old woman was just diagnosed withher first pregnancy. She enjoys good generalhealth. There is no h/o thyroid disease or Rx. Q: Should she have screening TFT? Thyroid 21:1081-1125, 2011

  8. What are the recommendations forTSH and T4 Screening in Pregnancy • Recommendation 72There is insufficient evidence to recommendfor or against universal TSH screening atthe 1st trimester visit • Recommendation 73Because no studies to date have demonstrated a benefit to treatment ofisolated maternal hypothyroxinemia,universal FT4 screening of pregnantwomen is not recommended Thyroid 21:1081, 2011

  9. Screening for Thyroid Disease in Pregnancy • Screening for subclinical hypothyroidism in pregnancy will be a cost-effective strategy under a wide range of circumstances. Thung et al: Am J Obstet Gynecol 2009 • Screening all pregnant women for autoimmune thyroid disease in the 1st trimester is cost-effective compared with not screening. Dosiou et al: EJE, 2008 • There are few prospective RCTs to substantiate the benefit of screening… the clinical epidemiological evidence does not justify universal screening at the present time. Lazarus J: Thyroid Res 2011 • Routine TSH screening before pregnancy or during the first trimester in all pregnant women. Gharib et al: Endocr Pract 2002

  10. 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 FHxthyroid disease • Goiter • TPOAb+ • Symptoms • Type 1 DM • Miscarriage • Other autoimmunedisease • Infertility • Morbid obesity • >30 years Thyroid 2011

  11. TSH in Pregnancy A 28-year-old woman who is 6 weekspregnant has a routine serum TSHlevel of 4.1 mIU/L & FT4 1.3 ng/dL Q: Is this TSH normal?

  12. 3.5 3.5 3.5 3.1 2.3 1.3 1.2 1.2 0.8 1.1 0.13 0.03 0.03 0.4 0.4 TSH Levels in Normal Pregnanciesn=343 Median and 95% TSH 4.5 3.5 2.5 TSH (mIU/L) 1.5 0.5 0.03 1st trimester 2nd trimester 3rd trimester 10 20 30 40 Weeks gestation Panesar NS et al: Ann Clin Biochem 32:329, 2001

  13. 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

  14. Guidelines for Serum FT4 During Pregnancy • Recommendation 3The optimal method to assess serum FT4 during pregnancyis measurement of T4 in the dialysate or ultrafiltrate of serum samples employing on-line extraction/liquid chromatography/tandem mass spectrometry (LC/MS/MS) • Recommendation 4If FT4 measurement by LC/MS/MS is not available, clinicians should use whichever measure or estimate of FT4 is available in their laboratory, being aware of the limitations of each method; serum TSH is a more accurate indication of thyroid status in pregnancy than any of these alternative methods • Recommendation 5In view of the wide variation in the results of FT4 assays, method-specific and trimester-specific reference ranges of serum FT4 are required

  15. Hypothyroidism in Pregnancy • Thyroid hormone is crucial for fetal brain development • Untreated congenital hypothyroidism is associated with low intelligence, impaired growth, cognitive and psychological disturbances (cretinism) • Hypothyroidism later in childhood is also associated with impaired growth, behavioral problems, symptoms of ADHD

  16. Thyroid and Pregnancy Physiologic consequences for the fetus • Fetal development – in particular that ofthe brain – is dependent on the thyroid function of the mother • The thyroid gland is not developed inthe fetus until 12th week • Thyroxine (T4) passes placenta, but relatively poorly

  17. SCH in Pregnancy A 26-year-old woman desires pregnancy; serum TSH is 4.5 mIU/L and FT4 1.0 ng/dL Questions: • Should you order TPOAb? • Should you Rx with T4 if TPOAbis positive? • What if TPOAb is negative?

  18. 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

  19. Why is it Important to diagnose Autoimmune Thyroid Disease in Pregnancy? • Most thyroid diseases in young women resultingin thyroid dysfunction are due to autoimmunity • Maternal thyroid dysfunction has adverse effects on the fetus • Improved treatment plan for the mother is beneficial to the fetus

  20. Anemia • Hypertension • Preeclampsia • Abruptio placenta • Postpartum hemorrhage • Miscarriage • Low birth weight • Stillbirth • Psychoneurologic impairment Effects of Hypothyroidism onPregnancy Outcomes Maternal Fetal JCEM, 2007

  21. Autoimmune Thyroidits • Hyperthyroidism • Graves’ disease • Hashitoxicosis • Euthyroidism • Symptom-free autoimmune thyroiditis • Hypothyroidism • Hashimoto’s thyroiditis • Atrophic thyroiditis

  22. D E L I V E R Y 40 30 20 10 0 10 20 30 40 TSH Changes in TPOAb (+) PregnantWomen During Gestation TSH 3mIU/I(in % of cases) Weeks of gestation Glinoer D et al: JCEM 79:197-204, 1994

  23. TPOAb and Hypothyroidism • Women with thyroid autoimmunity (i.e. positive TPOAb) who are euthyroid in the early stages of pregnancy are at risk of developing hypothyroidism • Should be monitored for elevation of TSH above the normal range

  24. 58 TPOAb +No treatment O U T C O M E 115TPOAb + 984pregnantwomen 57 TPOAb +LT4 869TPOAb- Treatment with LT4 in Pregnant Women with TAI: Effects on Obstetrical Complications 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 orTPOAb >1,500 kIU/L Negro R et al: JCEM 91:2587-2591, 2006

  25. Treatment with LT4 in Pregnant Women with TAI: Effects on Obstetrical Complications Miscarriage Preterm Delivery % Negro R et al: JCEM 91:2587-2591, 2006

  26. Study Conclusions • Under powered study • Neither placebo controllednor double blind • LT4 Rx reduced miscarriageand preterm delivery

  27. Autoimmune Thyroid Disease and Miscarriage • Many studies show increased miscarriage in euthyroid women with thyroid antibodies • Majority of studies demonstrate an association between thyroid antibodies and recurrent miscarriage • A causal relationship not established • Should we treat TPOAb+ women?

  28. 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)

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

  30. 30 articles with 31 studies (19 cohort and 12 case-control) involving 12,126 women assessed the association between thyroid autoantibodies and miscarriage.Cohort studies: OR 3.90 (95% confidence interval 2.48 to 6.12; P<0.001).Case control studies: OR 1.80 (1.25 to 2.60; P=0.002). There was a significant doubling in the odds of preterm birth with the presence of thyroid autoantibodies (2.07, 1.17 to 3.68; P=0.01). Conclusion: The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks. Thangaratinam S et al: BMJ 342:d2616, 2011 3162596-30

  31. SCHypo & Pregnancy • SCH (serum TSH concentration above the upper limit of the reference range with a normal free T4) has been shown to be associated with an adverse outcome for both the mother and offspring

  32. % Perinatal Outcomes inHypothyroid Pregnancies 68 women 23 with overt hypo 45 with SCH Overt Subclinical Control Leung AS et al: Obstet Gynecol 81:349, 1993

  33. Overt and Subclinical Hypothyroidism Complicating Pregnancy 51 pregnancies 16 overt hypo 35 subclinical hypo 60% abortion Rx inadequate 0% abortion Rx adequate 71% abortion Inadequate Rx 0% abortion Adequate Rx Adequate Rx – TSH <4 mIU/L Abalovich m et al: Thyroid 12:63, 2002

  34. Hypothyroidism & Pregnancy • 25,216 women with TSH screen retrospectively reviewed • All newborn euthyroid at birth • IQ scores of children born to mothers with slight TSH elevation were <7 points vs controls • Undiagnosed hypothyroidism in pregnancy adversely affects fetuses

  35. 21,846pregnant womenat 11-14 weeks Control Screen TSH >97.5th%FT4 <2.5th% T4Rx Follow IQ test in all children atage 3 were similar Lazarus et al: N Engl J Med 2012;366:493-501

  36. 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

  37. SCHypo and PregnancyTo Treat or Not To Treat? • Although efficacy of LT4 Rx has not been proved, given that the potential benefits outweigh the potential risks, T4 replacementis recommended

  38. Hypothyroidism & Pregnancy A 28-year-old woman has been on T4 for hypothyroidism for 5 years; she is now pregnant and taking LT4 125 mcg daily Q: What is optimal T4 dose and TSH level?

  39. 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

  40. Hyperthyroidism & Pregnancy A 32-year-old woman pregnant 10 weeks presents with nausea, vomiting, and a 2 kg weight loss; her first pregnancy 2 years earlier was uncomplicated On exam she is a bit dehydrated, euthyroid, without a goiter and has normal eyes TSH 0.01 (<2.5) FT4 2.1 (0.8-1.8) FT4I 20 (5-12) Q: Does she require antithyroid Rx?

  41. Hyperthyroidism & PregnancyClinical Clues in DDx

  42. Hyperthyroidism & PregnancyConclusions • Hyperemesis gravidarum is HCG-induced, reversible, and rarely requires ATD • Measure TSH receptor Ab (TRAb) to distinguish from Graves’ disease

  43. Hyperthyroidism & Pregnancy • Recommendation 22When serum TSH is suppressed (<0.1) inthe 1st trimester, FT4 should be obtained;TT3 & TRAb may also be helpful • Recommendation 26ATDs are not recommended for Rx of gestational hyperthyroidism

  44. Hyperthyroidism & Pregnancy A 32-year-old woman is 8 weeks pregnant; she reports palpitations, anxiety, heat intolerance and an 8 lb weight loss for 6 months On exam she is nervous, slightly hyperthyroid, has lid lag, and thyroid is x2 enlarged TSH 0.01FT4 2.8 FT4I 16 (5-12)TRAb 75% (<16%) Q: How do you manage?

  45. TSH receptorantibodies Stimulating T4 TSHreceptor Blocking T3 Stimulation Tg TSH Spencer CA 2006 3162596-47

  46. Mother Fetus Placenta TRH TRH TSH T3 T3 TSH T4 T4 Stimulate TSH receptorantibodies Block TPOAb & TgAb Anti-thyroiddrugs Block Spencer CA 2006

  47. Hyperthyroidism & Pregnancy • Thyroid autoantibodies (TRAb) cross placenta • Affect fetal thyroid after week 12 • Fetus can develop intrauterinemyxedema or hyperthyroidism evenif mother is euthyroid • Avoid combination T4/ATD Rx

  48. Hyperthyroidism & Pregnancy • Recommendation 28PTU is preferred for Rx of hyperthyroidismin the 1st trimester • Recommendation 29A combination of ATD and LT4 (block and replace) should not be used in pregnancy • Recommendation 30FT4 and TSH should be monitoredevery 2-6 weeks

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