Pregnancy & Thyroid. Zohreh Moosavi Associate professor of Endocriology Imam Reza General Hospital Mashad University. Imam Reza weeky Conferance

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1 Pregnancy & Thyroid Zohreh Moosavi Associate professor of Endocriology Imam Reza General Hospital Mashad University Imam Reza weeky Conferance

2 Objectives Thyroid Disorders & Pregnancy Normal thyroid phsyiology & pregnancy Hypothyroidism & pregnancy Thyrotoxicosis & pregnancy Postpartum thyroid dysfunction

3 Thyroid adaptation during normal pregnancy Change in thyroid physiology Change in thyroid function tests

4 Thyroid physiology Increase in thyroxine binding globulin Stimulation of the TSH receptor by HCG

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7 Thyroid Disease Spectrum Overt Hypothyroidism TSH >10 IU/mL, Free T 4 Low Subclinical Hypothyroidism TSH >2.5 IU/mL, Free T 4 Normal Euthyroid TSH IU/mL, Free T 4 Normal Hyperthyroidism TSH <0.2 IU/mL, Free T 3 /T 4 Normal or Elevated TSH, IU/mL.

8 Healthy pregnant women TSH = 0.03 to 0.1 mu/l

9 Trimester specific TSH First trimester Second Third 0.3-3

10 Hypothyroidism Overt Hypothyroidism elevated TSH, reduced free T4 Subclinical Hypothyroidism elevated TSH, normal free T4

11 Levothyroxine o.1 mg=100mcg Euthyrex 100 mcg, 50 mcg

12 Thyroid & Pregnancy: Hypothyroidism 85% will need increase in LT4 dose during pregnancy due to increased TBG levels (ave dose increase 48%) Risks: increased spont abort, HTN/preeclampsia, abruption, anemia, postpartum hemorrhage, preterm labour, baby SGA Fetal neuropsychological development (NEJM, 341(8): , Aug 31, 2001): Cognitive testing of children age 7-9 Untreated hyothyroid mothers vs. normal mothers: Average of 7 IQ points less in children Increased risk of IQ < 85 (19% vs. 5%) Retrospective study, data-dredging?

13 Thyroid peroxidase antibodies Anti TPO

14 LT4 dose adjustment in Pregnancy: - Optimize TSH preconception ( mu/l) - TSH at pregnancy diagnosis (~3-4 wk gestation), q1mos during 1 st 20 wks and after any LT4 dose change, q2mos 20 wks to term - Instruct women to take 2 extra thyroid pills/wk (q Mon, Thurs) for 29% dose increase once pregnancy suspected (+ commercial preg test) - If starting LT4 during preg: initial dose 2 ug/kg/d and recheck TSH q4wk until euthythyroid TSH Dose Adjustment TSH increased but < 10 Increase dose by 50 ug/d TSH TSH > 20 Increase dose by ug/d Increase dose by 100 ug/d

15 Goiter and Thyroid Nodules

16 Hyperthyroidism Overt Hyperthyroidism elevated free T4 and/ or free T3, Low TSH Subclinical Hyperthyroidism normal free T4, Low TSH

17 Thyrotoxicosis & Pregnancy Causes: Graves disease TMNG, toxic adenoma Thyroiditis Hydatiform mole Gestational hcg-asscociated Thyrotoxicosis Hyperemesis gravidarum hcg 60% TSH, 50% FT4 Resolves by 20 wks gestation Only Rx with ATD if persists > 20 wk

18 Graves Disease hcg-mediated (gestational transient thyrotoxicosis )

19 Indication for treatment Therapeutic options Goals of antithyroid drug therapy

20 Thyroid & Pregnancy: Normal Physiology Fetal thyroid starts working at wks T4 & T3 cross placenta but do so minimally Cross placenta well: MTZ > PTU TSH-R Ab (stim or block) ATD (PTU & MTZ): Fetal goitre (can compress trachea after birth) MTZ aplasia cutis scalp defects Other MTZ reported embryopathy: choanal atresia, esophageal atresia, tracheo-esophageal fistula Therefore do NOT use MTZ during pregnancy, use PTU instead

21 A good fetal outcome: Free T4 high normal range Lowest drug dose

22 Propylthiouracil ( PTU ) Methimazole Beta blockers

23 Dose and Monitoring T4 ( total ) mcg/dl TSH low normal

24 TSH High FT4 Low FT4 & FT3 High Low Low High 2 thyrotoxicosis Endo consult FT3, rt3 MRI, α-su 1 Hypothyroid If equivocal Central Hypothyroid TRH Stim. MRI, etc. 1 Thyrotoxicosis RAIU

25 Thyroid & Pregnancy: Normal Physiology Increased estrogen increased TBG (peaks wk 15-20) Higher total T4 & T3: normal FT4 & FT3 if normal thyroid fn. and good assay many automated FT4 assays underestimate true FT4 level (except Nichols equilibrium dialysis free T4 assay) if suspect your local FT4 assay is underestimating FT4 can check total T4 & T3 instead (normal pregnant range ~ 1.5x nonpregnant) hcg peak end of 1 st trimester, hcg has weak TSH agonist effect so may cause: slight goitre mild TSH suppression ( mu/l) in 9% of preg mild FT4 rise in 14% of preg

26 No TSH & FTI at end of 1 st trimester as expected from hcg effect Requirement to increase LT4 dose occurred between weeks 4-20 Despite exponential rise in estradiol throughout pregnancy (note y-axis units) TBG levels plateau at 20 wks

27 LT4 dose requirement tied to rising TBG levels (THBI inversely proportional to TBG level) By 10 wks need average increase of 29% LT4 dose By 20 wks need average increase of 48% LT4 dose No increase of dose beyond 20 wks required

28 * Regardless of cause of hypothyroidism (Hashimoto s, thyroidectomy) initial LT4 dose increase is usually required early (~ week 8), before 1 st prenatal visit!

29 Pregnancy: screen for thyroid dysfn? Universal screening not currently recommended: ACOG, AACE, Endo Society, ATA Controversial! Definitely screen: Goitre, FHx thyroid dysfn., prior postpartum thyroiditis, T1DM Ideally, check TSH preconception: mu/l: recheck TSH during 1 st trimester mu/l: do not need to recheck during preg If TSH not done preconception do at earliest prenatal visit: mu/l: hcg effect (9% preg), recheck in 5wk < 0.1 mu/l: recheck immediately with FT4, FT3, T4, T3

30 Thyrotoxicosis & Pregnancy Risks: Maternal: stillbirth, preterm labor, preeclampsia, CHF, thyroid storm during labor Fetal: SGA, possibly congenital malformation (if 1 st trimester thyrotoxicosis), fetal tachycardia, hydrops fetalis, neonatal thyrotoxicosis

31 Thyrotoxicosis & Pregnancy Diagnosis difficult: hcg effect: Suppressed TSH (9%) +/- FT4 (14%) until 12 wks Enhanced if hyperemesis gravidarum: 50-60% with abnormal TSH & FT4, duration to 20 wks FT4 assays reading falsely low T4 elevated due to TBG (1.5x normal) NO RADIOIODINE Measure: TSH, FT4, FT3, T4, T3, thyroid antibodies? Examine: goitre? orbitopathy? pretibial myxedema?

32 Pregnant & Suppressed TSH TSH < 0.1 TSH FT4, FT3, T4, T3 Thyroid Ab s Examine Still suppressed Recheck in 5 wks Normalizes Hyperemesis Gravidarum Very High TFT s: TSH undetectable very high free/total T4/T3 hyperthyroid symptoms no hyperemesis TSH-R ab + orbitopathy goitre, nodule/tmng pretibial myxedema Don t treat with PTU Abnormal TFT s past 20 wk Treat Hyperthyroidism (PTU)

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34 Case 1 31 year old female G2P1A0, 11 weeks pregnant Well except fatigue Hb 108, ferritin 7 (Fe and LT4 interaction?) TSH 0.2 mu/l, FT4 7 pm Started on LT TSH < 0.01 mu/l FT4 12 pm, FT3 2.1 pm

35 Thyrotoxicosis & Pregnancy: Rx No RAI ever (destroy fetal thyroid) PTU Start 100 mg tid, titrate to lowest possible dose Monitor qmos on Rx: T4, T3, FT4, FT3 TSH less useful (lags, hcg suppression) Aim for high-normal to slightly elevated hormone levels T nm, T nm, FT pm 3 rd trimester: titrate PTU down & d/c prior to delivery if TFT s permit to minimize risk of fetal goitre Consider fetal U/S wk to R/O fetal goitre If allergy/neutropenia on PTU: 2 nd trimester thyroidectomy

36 Thyrotoxicosis & Lactation ATD generally don t get into breast milk unless at higher doses: PTU > mg/d MTZ > 20 mg/d Generally safe I prefer PTU > MTZ for preg lactating Take ATD dose just after breast-feeding Should provide 3-4h interval before lactates again

37 Neonatal Grave s Rare, 1% infants born to Graves moms 2 types: Transplacental trnsfr of TSH-R ab (IgG) Present at birth, self-limited Rx PTU, Lugol s, propanolol, prednisone Prevention: TSI in mom 2 nd trimester, if 5X normal then Rx mom with PTU (crosses placenta to protect fetus) even if mom is euthyroid (can give mom LT4 which won t cross placenta) Child develops own TSH-R ab Strong family hx of Grave s 3-6 mos 20% mortality, persistant brain dysfunction

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39 Postpartum & Thyroid 5% (3-16%) postpartum women (25% T1DM) Up to 1 year postpartum (most 1-4 months) Lymphocytic infiltration (Hashimoto s) Postpartum Exacerbation of all autoimmune dx 25-50% persistant hypothyroidism Small, diffuse, nontender goitre Transiently thyrotoxic Hypothyroid

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41 Postpartum & Thyroid Distinguish Thyrotoxic phase from Grave s: Rx: No Eye disease, pretibial myxedema Less severe thyrotoxic, transient (repeat thyroid fn 2-3 mos) RAI (if not breast-feeding) Hyperthyroid symptoms: atenolol mg od Hypothyroid symptoms: LT ug/d to start Adjust LT4 dose for symtoms and normalization TSH Consider withdrawal at 6-9 months (25-50% persistent hypothyroid, hi-risk recur future preg)

42 Postpartum & Thyroid Postpartum depression When studied, no association between postpartum depression/thyroiditis Overlapping symtoms, R/O thyroid before start antidepressents Screening for Postpartum Thyroiditis HOW: TSH q3mos from 1 mos to 1 year postpartum? WHO: Symptoms of thyroid dysfn. Goitre T1DM Postpartum thyroiditis with prior pregnancy