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Thyroid Disease in Pregnancy 2011 Update. Endocrinology Rounds February 16, 2011 Selina Liu PGY5 Endocrinology. Objectives. To briefly review thyroid anatomy and physiology in pregnancy and fetal thyroid physiology To review causes of thyroid disease in pregnancy

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Thyroid Disease in Pregnancy 2011 Update


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    1. Thyroid Disease in Pregnancy2011 Update Endocrinology Rounds February 16, 2011 Selina Liu PGY5 Endocrinology

    2. Objectives • To briefly review thyroid anatomy and physiology in pregnancy and fetal thyroid physiology • To review causes of thyroid disease in pregnancy • To review the maternal and fetal outcomes of thyroid disease in pregnancy • To discuss the controversy surrounding screening for thyroid disease in pregnancy

    3. Objectives • To review special considerations in management of thyroid disease in pregnancy • To highlight recent 2009-2011 articles published on thyroid disease in pregnancy

    4. Thyroid in Pregnancy • non-pregnant: 10-30 g (North America) • in pregnancy, • increased vascularity • thyroid gland hyperplasia • if enlargement noted incidentally on exam, may lead to lab evaluation of thyroid function • normal pregnancy - significant but reversible changes in maternal thyroid physiology

    5. Total T4: 150 % above normal non-pregnant reference interval Casey BM & Leveno KJ. Obstet Gynecol 2006;1081283-9

    6. Clinical Importance of Physiological Changes • Increased TBG • Placental de-iodination of T4 • Increased iodine clearance (renal clearance and fetal transfer) • Need for  T4 production •  total T4, T3 • interference with fT4 assay • Need for  T4 production •  T4 and T3 metabolism •  need for iodine supplementation • risk of maternal & fetal hypothyroidism and goitre Keely E & Casey BM (2010). Thyroid disease in pregnancy. In RO Powrie, MF Greene, W Camann (Eds) deSwiet’s Medical Disorders in Obstetric Practice (5th Edition pp322-34). West Sussex, Wiley-Blackwell

    7. Clinical Importance of Physiological Changes •  bhCG (1st trimester) •  TSH-R Abs (TSI/TBII) •  thyroid antibodies (post-partum) •  fT4 and  TSH • may have mild transient thyrotoxicosis • Graves’ disease may improve during pregnancy • exacerbation of Graves’ disease • precipitation of postpartum thyroiditis Keely E & Casey BM (2010). Thyroid disease in pregnancy. In RO Powrie, MF Greene, W Camann (Eds) deSwiet’s Medical Disorders in Obstetric Practice (5th Edition pp322-34). West Sussex, Wiley-Blackwell

    8. Fetal Thyroid Physiology • 12 weeks gestational age: • embryogenesis of fetal thyroid gland is complete • synthesis of thyroid hormone • fetal TSH also detectable • Mid-gestation: • negative feedback control of thyroid hormone synthesis develops • Throughout gestation: • pituitary-thyroid axis continues to develop

    9. Fetal Thyroid Physiology What crosses the placenta? • iodine • T3, T4 (poorly) – but large maternal–fetal gradient • maternal TRH – but negligible amount in maternal circulation • TSH-R antibodies (TSI/TBII) • anti-thyroid medication – methimazole, PTU Maternal TSH does NOT cross the placenta

    10. Fetal Thyroid Physiology Prior to 12 weeks gestation, • fetus dependent on maternal thyroid hormone production • critical time for fetal neural development (as well as later in gestation) Throughout pregnancy, • T4 and iodine supplied by mother to fetus • maternal iodine supply very important throughout • unclear role of maternal T4 after fetal T4 production begins

    11. Thyroid Disease in Pregnancy • Hyperthyroidism • Hypothyroidism • Post-partum Thyroiditis • Thyroid Nodules

    12. Graves’ Disease • toxic nodule/MNG • thyroiditis • exogenous iodine • TSHoma • struma ovarii • gestational transient thyrotoxicosis • hyperemesis gravidarum • gestational trophoblastic disease • familial gestational thyrotoxicosis non hCG-mediated hCG-mediated Hyperthyroidism in Pregnancy • ~ 0.2% of pregnancies complicated by hyperthyroidism • Causes:

    13. (developed world) (worldwide) Hypothyroidism in Pregnancy • overt hypothyroidism ~ 0.1-0.3% of pregnancies • subclinical hypothyroidism ~ 3-5% of pregnancies • Causes: • Hashimoto’s Thyroiditis • iodine deficiency • prior RAI ablation/thyroidectomy • medications (lithium, amiodarone) • central hypothyroidism (rare) ? genetic susceptibility

    14. Subclinical Hypothyroidism • TSH variable ~ 40-60% of TSH variability under genetic control? • Genome Wide Association Scanning: • SNP in PDE 8B gene associated with circulating TSH levels • PDE 8 B – catalyzes hydrolysis of cAMP • responsible for 2.3% of variance in TSH • each copy of allele present – associated with an increase in TSH concentration of 0.13 mIU/L Arnaud-Lopez L et al. 2008 Am J Hum Genet 82:1270-80

    15. Subclinical Hypothyroidism – PDE8B Arnaud-Lopez L et al. 2008 Am J Hum Genet 82:1270-80

    16. 1014 healthy pregnant women at 28 wks • TFTs, anti-TPO, PDE8B genotype (AA, AG, GG) • developed reference range (based on anti-TPO – subjects) • TSH 0.49-4.21 mIU/L • AA group had highest, GG group had lowest TSH • AA group - greater proportion with TSH >4.21 mIU/L (ULN)

    17. SNP in PDE8B associated with  TSH - AA highest, GG lowest • no difference in fT3, fT4 or prevalence of anti-TPO + Abs

    18. Post-partum Thyroiditis (PPT) • due to rebound autoimmunity post-partum • lymphocytic infiltration, transient changes in thyroid function • + anti-TPO in >90% women with PPT • those with high titres in early pregnancy more likely to be affected (50-60%) • high incidence in T1DM (18-25%) • (high prevalence anti-TPO)

    19. Post-partum Thyroiditis (PPT) Pearce EN et al. 2003 N Engl J Med 348:2646-55

    20. Thyroid Nodules in Pregnancy • nodule > 1cm – FNAB • if 1st or early 2nd trimester and malignant OR rapid growth, offer surgery in 2nd trimester • if follicular or papillary, no advanced disease – can defer surgery until post-partum • can suppress TSH if: previously treated thyroid cancer, FNAB suspicious or positive for malignancy, or if delaying surgery until post-partum • to detectable levels (keep fT4 in normal range) J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47

    21. Thyroid Nodules in Pregnancy • RAI with I131 should NOT be given to pregnant women or those breastfeeding • women with thyroid cancer treated with therapeutic doses of RAI should avoid pregnancy for 6-12 months post-ablation J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47

    22. Maternal Outcomes - Hyperthyroidism • increased risk of: • spontaneous pregnancy loss • CHF • thyroid storm • preterm birth • preeclampsia • perinatal morbidity & mortality

    23. Fetal Outcomes – Maternal Hyperthyroidism • depends on degree of thyrotoxicosis, cause, and treatment of mother • in most cases, fetus is euthyroid • but, transplacental transfer of TSH-R Abs (TSI/TBII) can cause fetal Graves’ disease • 1-10% of neonates of affected women • risk directly related to maternal Ab titre in 3rd trimester • manifestations: • fetal tachycardia • high output heart failure • hydrops fetalis • craniosynostosis • IUGR • fetal goitre

    24. Fetal Outcomes – Maternal Hyperthyroidism Endocrine Society Clinical Practice Guidelines 2007 • measure TSH-R Abs prior to pregnancy or before end of 2nd trimester in women with: • current Graves’ Disease • prior history of Graves’ Disease and I131 treatment or thyroidectomy • previous neonate with Graves’ Disease • if – TSH-R Abs and don’t require anti-thyroid Rx • low risk of fetal/neonatal thyroid dysfunction J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47

    25. Fetal Outcomes – Maternal Hyperthyroidism • if + TSH-R Abs, need close fetal monitoring: • fetal heart rate at each OB visit - ?tachycardia • fetal ultrasound – assess growth, ?goitre – especially if mother on anti-thyroid medication • consider serial U/S q2-4 wks in 3rd trimester – if very high TSH-R Abs titres • ? fetal blood sampling for thyroid indices – not routine • if high maternal TSH-R Abs, evidence of IUGR, fetal CHF, or fetal goitre J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47 ACOG Practice Bulletin Obstet Gynecol 2002, 100(2):387-396

    26. Maternal Outcomes - Hypothyroidism • increased risk of: • early pregnancy failure • preeclampsia • placental abruption • treatment of women with overt hypothyroidism associated with improved pregnancy outcomes

    27. Fetal Outcomes – Maternal Hypothyroidism • increased risk of: • low birthweight • stillbirth • intellectual impairment • especially if overt maternal hypothyroidism in 1st trimester

    28. Outcomes – Subclinical Thyroid Disease • less clear effect of: • subclinical hypo/hyperthyroidism • euthyroid thyroid autoimmunity (+ autoantibodies) • maternal hypothroxinemia • normal TSH but low fT4 on both maternal and fetal outcomes

    29. population-based cohort - Netherlands • 3659 children and their mothers (Apr/02-Jan/06) • examined association between early pregnancy thyroid function and cognitive function in early childhood • maternal TFTs (mean 13.3 wk GA) • verbal/nonverbal cognitive development – as per mailed parent-report measures (18 and 30 months) • specifically looked at maternal hypothyroxinemia (normal TSH, but fT4)

    30. TSH range 0.35-2.5 fT4 11-25 (non-preg) Hypothyroid TSH>2.5, fT4 <11 Hyperthyroid TSH <0.03, fT4>25 Mild hypothyroxinemia Normal TSH fT4 <11.76 (10th %ile) Severe hypothyroxinemia Normal TSH fT4 < 10.96 (5th %ile)

    31. mild hypothyroxinemia significantly related to expressive language delay across ages • severe hypothyroxinemia predicted  likelihood of expressive language delay at 18m, 30m, and across ages

    32. severe hypothyroxinemia predicted  likelihood of nonverbal cognitive delay at 30m

    33. Conclusions: • maternal hypothyroxinemia predicted a higher risk of verbal and nonverbal cognitive delay in early childhood • maternal TSH did not predict cognitive outcomes • need more studies assessing potential benefit of iodine or T4 supplementation in early pregnancy before can justify implementation of fT4 screening in early pregnancy

    34. Screening in Pregnancy ? • What is a normal TSH in pregnancy? • Gestational age-specific TSH reference range? • several studies, in variety of populations • reference ranges in non-pregnant populations are not applicable to pregnancy

    35. Gestational Age-Specific TSH Range • Dashe JS et al. 2005 Obstet Gynecol 106:753-7 • 13 731 pregnancies • 13 599 singleton and 132 twin pregnancies • measured TSH • assay reference 0.4 – 4 • created nomogram based on gestational age

    36. 342 women (singleton) with TSH above 97.5%ile 95 (28%) would not have been identified with TSH elevation as per assay reference value 340 women (singleton) with TSH below 2.5%ile 1448 (11%) euthyroid women would have been incorrectly characterized as abnormal as per assay reference value Dashe JS et al. 2005 Obstet Gynecol 106:753-7

    37. Gestational Age-Specific TSH Range • Gestational-age specific normal TSH range • converted TSH values to MoM “multiples of median” to facilitate use in other populations Dashe JS et al. 2005 Obstet Gynecol 106:753-7

    38. goal – to calculate gestational age-specific TSH, fT4 and fT3 reference intervals in an iodine sufficient, thyroid antibody-negative population • also – to establish association between BMI and fT4, fT3 • prospective population-based cohort • Northern Finland Birth Cohort 1986 (9632 singleton births) Thyroid 2011 Jan 22 epub ahead of print

    39. 0.35 Assay reference range TSH 0.35-4.94 Thyroid 2011 Jan 22 epub ahead of print

    40. 19 5.7 Assay reference range fT4 9-19 Assay reference range fT3 2.62-5.7 Thyroid 2011 Jan 22 epub ahead of print

    41. 95%ile selected as upper limit • therefore, upper limit of 2.7-3.1 mU/L in 1st trimester and 2.8-3.5 mU/L in early 2nd trimester Thyroid 2011 Jan 22 epub ahead of print

    42. TSH increases and fT4 decreases with increasing BMI • fT3 increases with increasing BMI Thyroid 2011 Jan 22 epub ahead of print

    43. Screening in Pregnancy? • YES - ? potential harm to fetus if undiagnosed thyroid disease • NO – ? unclear benefits of screening in preventing adverse events • screening of only high-risk women failed to detect 30% of hypothyroid and 69% of hyperthyroid women Vaidya B et al. 2007 J Clin Endocrinol Metab 92:203-7

    44. 4562 women, 2 centres in Italy • randomized to universal screening or case-finding • stratified as high risk or low risk • all women in universal screening group, and high risk women in case-finding group, had TSH, fT4, antiTPO • low risk women in case-finding group: • serum frozen, tested post-partum • Rx LT4 if TSH >2.5 if +anti-TPO, or Rx antithyroid medication if hyperthyroid J Clin Endocrinol Metab 2010 95(4):1699-707

    45. J Clin Endocrinol Metab 2010 95(4):1699-707

    46. No difference in total number of adverse outcomes in case finding vs screening • Majority of adverse outcomes in euthyroid groups J Clin Endocrinol Metab 2010 95(4):1699-707

    47. Interaction between thyroid status and trial arm: • low risk women: adverse outcomes less likely in screening vs case finding • inferred NNT = 1.8 36/39 had at least 1 adverse outcome 19/51 had at least 1 adverse outcome J Clin Endocrinol Metab 2010 95(4):1699-707

    48. J Clin Endocrinol Metab 2010 95(4):1699-707

    49. universal screening vs case-finding did not result in less adverse outcomes • BUT - low risk women in universal screening group with abnormal thyroid function (who were treated) avoided adverse outcomes more often than low risk women in case finding group with abnormal thyroid function (not detected, so not treated) J Clin Endocrinol Metab 2010 95(4):1699-707

    50. Screening in Pregnancy? • CATS study – Controlled Antenatal Thyroid Screening • multicentre, prospective randomized trial in UK from 2002-2010 • ~ 22 000 women, blood drawn prior to 16 wks GA • before testing, randomized to “screening” or “control” • screening group – tested, and if TSH or  fT4 – Rx LT4 • control group – tested post-partum, and if TSH or  fT4 – Rx LT4 post-partum • 1o outcome: children’s IQ at 38-40 months - no difference