Thyroid Disease in Pregnancy

1. Thyroid DiseaseinPregnancy Josephine Carlos-Raboca, MD, FPCP, FPSEM Section of Endocrinology, Diabetes and Metabolism Makati Medical Center

2. Outline • Thyroid Physiology in Pregnancy Maternal Fetal • Gestational Thyrotoxicosis • Grave’s Disease in Pregnancy • Hypothyroidism • Postpartum thyroiditis

3. H - P Thyroid Axis

4. Maternal Physiology • Thyroid circulation • Thyroxine clearance rate • Dietary iodine requirement • hCG mediated thyroid stimulation

5. Thryoxine binding globulin(TBG) • Increased serum (TBG) due to estrogen induced sialylation of the protein which leads to decreased renal clearance and longer half life ( from normal 15 minutes, increased to 3 days)

6. Effects of Increased TBG • Increased total T3 and total T4 • Free hormone assay are thus preferred • FT4I should be done if free hormone determination is not available

7. Thyroid Disposal/Clearance • Iodinase Type 1 – liver, kidney, thyroid converts T4 to T3 Type 2 - pituitary, brown fat, brain converts T4 to T3 Type 3 – placenta brain and skin converts T4 to rT3 and T3 to T2

8. Increased demand for iodine • Increased GFR • Increased iodide clearance by the kidney • Siphoning of maternal iodide by the fetus • WHO: RDA 200 ug/day during pregnancy

9. Increased demand for thyroid hormones • Increased iodide clearance • Transplacental transfer of T4 and iodine • Placental degradation of T4

10. Thyroid stimulation by chorionic gonadotropin • Similarity of TSH and HCG • alpha subunit is common to TSH, hCG, FSH and LH • Beta subunit is specific but some similarity in TSH and hCG • HCG stimulates TSH receptor has weak thyrotropic activity 1/10000 of TSH

11. Thyroid stimulation by hCG

12. Physiologic change Increased TBG First trimester hCG elevation Increased plasma volume Increased plasma type 3 deiodinase Thyroid enlargement Increased iodine clearance Thyroid function test change Elevation of T4 and T3 Elevated FT4 and suppressed TSH Increased T4 and T3 pool size Potential increased T4 and T3 degradation Increased serum Tg Reduced hormone production in iodine insufficient Physiologic changes in pregnancy and thyroid function test

13. Fetal Ontogeny and Physiology • T3 dependent CNS development • Thyroid organogenesis, iodine concentration and hormonogeneiss • Dependence on maternal iodothyronines

14. Thyroid Deficiency in the Fetus and Neonate • 2 sources of thyroid hormones in fetus • Fetal thyroid which begins synthesis at 10 – 12 weeks • Maternal thyroid hormones -current evidence shows substantial transfer across the placenta -placenta contains deiodinase that converts T4 to T3

15. Thyroid Tests Thyroid Hormones – TT3,TT4, FT3, FT4 FT4I, TSH Thyroid antibodies TPOAb,TgAb, TSHRAb (TSI,TBII)

16. Hyperthyroidism • Etiologies • Clinical presentations • Diagnosis • Maternal and fetal consequences • Therapeutic options

17. Hyperthyroidism • Occurs in 1-2/1000 pregnancies

18. Causes of hyperthyroidism in pregnancy • Grave’s Disease • Gestational Thyrotoxicosis • Hydatidiform mole • Silent Thyroiditis • Multinodular toxic goiter • Toxic adenoma • Subacute thyroiditis • Iatrogenic hyperthyroidism\Iodine induced hyperthyroidism

19. Case 1 • Leah a 25 year old G1P0 female was confined on her 10th week of gestation because of nausea and vomiting several times daily requiring parenteral fluids. She was referred to you for endocrine evaluation. 2 weeks earlier she was confined for the same problem and gastroscopy was done which was negative.

20. Case 1 • She has not had any weight gain since start of pregnancy. She had no history of thyroid problem. PE showed no goiter, no tremors nor eye signs. BP was normal. Pulse rate was 92/minute and was afebrile.

21. Thyroid Function tests • FT3 RIA 4.74 pmol/l (4.2-12) • FT4 RIA 25 pmol/l (8.8-33) • TSH IRMA 0.08 uIU/ml (0.35 – 5.0)

22. Question • What is your likely diagnosis? differential diagnosis?

23. Conditions with suppressed TSH • Increased thyroid hormone production Grave’s Disease Autonomous Thyroid nodule Hyperemesis gravidarum Molar Pregnancy First trimester pregnancy

24. Conditions with Suppressed TSH • Normal or Low Thyroid Production • Post therapy of hyperthyroidism • Pituitary/hypothalamic disease • Severe nonthyroidal illness

25. Gestational Thyrotoxicosis • Spectrum of hCG-induced hyperthyroidism which ranges from an isolated subnormal TSH concentration(up to 18%) to elevation of free thyroid hormone levels in the clinical setting of hyperemesis gravidarum

26. Question 2 • Will you treat? • Treatment is not generally recommended. • Is vomiting related to hyperthyroidism? • Not likely • Vomiting seen in hypothyroid, euthyroid and hyperthyroid, probably related to hCG induced elevation of estradiol

27. Question 3 How will you follow up? • Repeat thyroid function tests after 20th week • If persistent hyperemesis and elevated thyroid hormones and suppressed TSH after 20 weeks of gestation consider antithyroid treatment as this may be mild Grave’s disease.

28. Gestational Thyrotoxicosis • Transient • Symptoms usually resolve within 10 weeks of diagnosis • Differs from Grave’s • Non-autoimmune etiology (hCG induced) with negative anti thyroid and anti TSH receptor antibody • Negative goiter • Resolution in almost all patients after 20 weeks of gestation • No ophthalmopathy

29. Case 2 Luisa a 30 year old G2P1 female was referred to you on her 12th week of pregnancy because of hypertension, palpitations and weight loss of 5 lbs since start of pregnancy. BP was 145/95 despite bed rest. Cardiologist gave apresoline 10 mg tid. Urinalysis was negative for protein.

30. Case 2 Prominent eyes were noted so endocrine referral was sought. Further history taking revealed hyperthyroidism 3 years ago with ATD treatment for 1 year. On PE, BP was 140/90 PR 110/minute, with positive lid retraction, diffuse goiter and bruit and fine hand tremors. No leg edema

31. Thyroid tests • FT3 RIA 15 pmol/l ( 4.2-12) • FT4RIA 55 pmol/l (8.8 – 33) • TSH-IRMA 0.002 uIU/L (0.35-5.0)

32. Question 1 • What is your likely diagnosis? • Chronic hypertension • Grave’s – eye signs, goiter, bruit

33. Diagnosis of Grave’s • Symptoms of hypermetabolic state • Sometimes goiter with bruit • Eye signs • Elevated free T3 and freeT4 • Suppressed TSH • RAIU elevated(not done in pregnant) • Elevated TgAb and TPOAb • TSH-R Ab positive

34. Grave’s Hyperthyroidism • Positive thyroid antibodies TPOAb TgAb TSHRAb (TSI) • Unusual to present for the first time in pregnancy • Symptoms usually antedate pregnancy for a few months

35. Question 2 • What are other tests are useful to confirm your diagnosis if available? • TPOAb • TgAb • TSHRAb/TSI – to differentiate from silent thyroiditis

36. Question 3 • What is your treatment of choice?

37. Which ATD is best? PTU favored because: • MMI has been associated with aplasia cutis a congenital scalp defect (Mandel 1994 Thyroid 4:129-133) • PTU is heavily protein bound and believed to cross placenta less • 6 women without history of thyroid disease received a single injection of either (35S)MMI or PTU in the first half of pregnancy prior to a therapeutic abortion (Marchant 1977 JCEM 45:1187-1193)

38. Which ATD is best? • an in vitro study showed two drugs equally passed placental barrier (Mortimer 1997 JCEM 82:3099) • no prospective RCTs compared maternal and fetal outcome; • retrospective case series have shown that the rate of fetal hypothyroidism is similar with both drugs (Wing 1994 Am J Obstet Gynecol 170:90)

39. What is the dose of ATD in pregnant? • Initial dose may vary according to severity of maternal hypothyroidism • Use the lowest dose possible to maintain maternal euthyroidism 15-10 mg MMI or 300 mg PTU • In 30% ATD may be discontinued in last trimester

40. Effect of ATD overdose on fetus • fetal goiter which may lead to respiratory distress • Intrauterine growth retardation • 4 studies showed no defects in either cognitive or somatic development of children exposed to maternal ATD in utero but maternal thyroid hormone levels not known

41. Duration of action short long Potency less more Placental passage about 1 prob 1 Breast milk less more Toxicity aplasia cutis Other blocks T4 to T3 PTU vs MMI

42. Question 4 • What are your treatment goals?

43. Guidelines for clinical management of maternal hyperthyroidism during pregnancy • Use the lowest dose of ATDs to maintain maternal thyroid hormone levels in the upper 1/3 of the normal range to slightly elevated during pregnancy.(FT4 23-25 pmol/l or 1.8-2.0 ng/dl)

44. Guidelines for clinical management of maternal hyperthyroidism during pregnancy • Check maternal thyroid hormone levels monthly, using free T4 levels • Measure TSI/TBII at 26-28 weeks • Consider fetal ultrasound at 26-28 weeks if the TSI/TBII levels are elevated or if Doppler detects fetal tachycardia

45. Other forms of treatment • Beta adrenergic blockers –may be used transiently to control adrenergic symptoms ( small series where propranolol was prescribed for 6-12 weeks reported higher rates of miscarriages) • Iodides should not be used but may be used if needed to prepare for thyroidectomy • Surgery in latter half of second trimester

46. Question 5 • What are maternal and fetal consequences of hyperthyroidism?

47. Pregnancy complications reported in hyperthyroid women • Maternal • pre-ecclampsia(14% if untreated vs 6%for treated) • Gestational hypertension • pregnancy-induced hypertension • placental abruption • Congestive heart failure(63% if untreated) • Preterm labor(88% if untreated; 25% partial treatment 8% if adequate treatment)

48. Other potential complications of uncontrolled hyperthyroidism Maternal • Anemia • Miscarriage • Thyroid storm Fetal prematurity

49. Pregnancy complications reported in hyperthyroid women • Fetal • Small for gestation age • Intrauterine growth retardation • Stillbirth (50% if untreated, 16% partial treatment) • Fetal/neonatal hyperthyroidism

50. Case 3 • Marissa a 32 year old G5P2 Ab2 female was referred on her 8th weeks of pregnancy because of easy fatigability and hypertension. Her weight gain was 5 lbs in 8 weeks.