Thyroid Disease in Pregnancy: The Essentials. Elizabeth N. Pearce, MD, MSc

Thyroid Disease in Pregnancy: The Essentials Elizabeth N. Pearce, MD, MSc

None Disclosures

Case 1

A 31-year-old woman from Massachusetts is practicing a vegan diet. She is currently planning a pregnancy. She has no history of thyroid disease. She has no goiter. Exam findings are normal. Her serum TSH level is 1.9 miu/l. Which of the following should you recommend? A. Change to a diet containing animal products B. Add twice-weekly kelp to current diet C. Start a daily prenatal supplement containing 150 µg iodine D. Change from iodized table salt to sea salt

U.S. and European Guidelines Women who are planning to be pregnant or are pregnant or breastfeeding should supplement their diet with a daily oral supplement that contains 150 µg of iodine. Alexander EK, Pearce EN, et al. Thyroid 2017;27:315-389 De Groot L et al. J Clin Endocrinol Metab 2012;97:2543-65 SG Obican et al. Birth Defects Res A Clin Mol Teratol 2012;94: 677-682 AAP Council on Environmental Health. Pediatrics 2014;133:1163-6 JH Lazarus et al. Eur Thyroid J 2014;3:76-94.

Case 2

A 29 yo F presents at 9 weeks gestation. She has no history of thyroid disease. Her serum TSH is 3.4 miu/l. Is this a normal TSH value?

TSH in the First Trimester is Inversely Related to Serum hcg 4.0 hcg 30 50 TSH miu/l 3.0 2.0 Free T4 pmol/l 25 20 15 10 20 40 60 80 100 hcg (I.U./Lx1000) 40 30 hcg IU/L X 10 3 20 1.0 10 0.1 1st. Trimester 2nd. Trimester 3rd. Trimester 0 weeks gestation 10 20 30 40 Glinoer et al. J Clin Endocrinol Metab 1990;71:276

Trimester-Specific TSH Ranges Based on n= 5,486 Negro & Stagnaro-Green BMJ 2014;349:g4929

n = 51,785 Alexander EK, Pearce EN, et al. Thyroid 2017;27(3):315-389

ATA Guideline 2017 When possible, trimester-specific reference ranges for serum TSH should be defined through assessment of local population data representative of a healthcare provider s practice. Reference range determinations should only include pregnant women with no known thyroid disease, optimal iodine intake, and negative TPO Ab status. (Strong Recommendation, Moderate Quality Evidence) Alexander EK, Pearce EN, et al. Thyroid 2017;27(3):315-389

ATA Guideline 2017 If internal or transferable pregnancy-specific TSH reference ranges are not available, an upper reference limit of ~ 4.0mU/l may be used. For most assays, this represents a reduction in the nonpregnant TSH upper reference limit of ~0.5mIU/L. (Strong Recommendation, Moderate Quality Evidence) Alexander EK, Pearce EN, et al. Thyroid 2017;27(3):315-389

A 29 yo F presents at 10 weeks gestation. She has no history of thyroid disease. She has no goiter. Her serum TSH is 3.4 miu/l. What is the next best step? A. Repeat the TSH in 4 weeks B. Check a TPO antibody C. Start levothyroxine 50 mcg daily

Combined Effects of Subclinical Hypothyroidism and Thyroid Autoimmunity Prospective observational cohort, n=3,315, China Group OR for miscarriage (95% CI) SCH1 (TSH 2.5-5.22) 1.62 (0.96, 2.73) SCH2 (TSH 5.22-10) 3.40 (1.62, 7.15) TAI (+ for TPO Ab +/- TG 2.71 (1.43, 5.12) Ab) SCH1 + TAI 4.96 (2.76, 8.90) SCH2 + TAI 9.56 (3.76, 24.28) H Liu et al, Thyroid 2014; 24(11):1642-9

ATA Guideline 2017 Cooper DS & Pearce EN. N Engl J Med 2017;376:876-7 Alexander EK, Pearce EN, et al. Thyroid 2017;27(3):315-389

Case 3

A 37 yo woman presents with palpitations and tremor at 8 weeks gestation. She has no history of thyroid disease. She has no nausea, vomiting, or abdominal pain. Her heart rate is 106 beats/min, and she has no ophthalmopathy. The thyroid is nontender, upper limit of normal size, without bruit or palpable nodules. TSH 4 months ago: 0.54 miu/l Labs now: TSH 0.014 miu/l free T4 1.59 ng/dl (ref 0.7-1.9 ng/dl) What do you recommend: A. Start PTU B. Start methimazole C. Repeat labs in 4 weeks D. Radioactive iodine uptake and scan E. Obtain a TRAb

Thyroid Function Changes with Hyperemesis 3.0 TSH 4 Free T4 hcg TSH miu/l 2.5 2.0 1.5 1.0 0.5 3 FT4 ng/dl 2 1 120 hcg IU/Lx10 3 80 40 0.01 0 0 No Vomiting Vomiting Hyperemesis Severe Hyperemesis Goodwin et al. JCEM 1992;75:1333-7

She returns for labs at 12 and then at 16 weeks gestation: Prepregnancy 8 Weeks Gestation 12 Weeks Gestation 16 Weeks Gestation TSH Free T 4 Reference range 0.7-1.9 0.54 miu/l 0.014 miu/l <0.008 miu/l <0.008 miu/l 1.59 ng/dl 1.79 ng/dl 1.90 ng/dl Total T 3 Reference range 80-180 What is the most likely diagnosis? A.Gestational thyrotoxicosis B.Graves disease 264 ng/dl 269 ng/dl

She returns for labs at 12 and then at 16 weeks gestation: Prepregnancy 8 Weeks Gestation 12 Weeks Gestation 16 Weeks Gestation TSH Free T 4 Reference range 0.7-1.9 0.54 miu/l 0.014 miu/l <0.008 miu/l <0.008 miu/l 1.59 ng/dl 1.79 ng/dl 1.90 ng/dl Total T 3 Reference range 80-180 What is the most likely diagnosis? A.Gestational thyrotoxicosis B.Graves disease 264 ng/dl 269 ng/dl Thyroid stimulating immunoglobulin at 12 weeks: 210% (normal <130)

Prepregnancy 8 Weeks Gestation 12 Weeks Gestation 16 Weeks Gestation TSH Free T 4 Reference range 0.7-1.9 Total T 3 Reference range 80-180 0.54 miu/l 0.014 miu/l <0.008 miu/l <0.008 miu/l 1.59 ng/dl 1.79 ng/dl 1.90 ng/dl 264 ng/dl 269 ng/dl Thyroid stimulating immunoglobulin at 12 weeks: 210% (normal <130) How should she be treated? A.Start PTU B.Start methimazole C.Repeat testing in 4 weeks

Serum Total T4 Serum Total T3 Serum rt3 16 weeks Guidelines to Use Total T4 or T3 Measurement During Pregnancy The increase in Total T4 occurs weeks 7-16 and is then sustained throughout pregnancy Gestational-week specific values can be calculated as 5% above normal per week in weeks 7-16, 50% above normal 17-40 J Weeke et al. Acta Endocrinologica 1982;101:531-7.

No Complications Associated with Subclinical Hyperthyroidism (SCHY) ( TSH < 2.5 percentile for gestational age) Maternal Fetal/Neonate 25 12 20 Euthyroid controls (n = 23,124) SCHY (n = 433) 10 % 15 10 8 6 4 % 5 2 0 1 2 3 4 5 6 7 8 1. Gestational hypertension 2. Severe preeclampsia 3. Diabetes 4. Placental abruption 5. 36 weeks gestation 6. 34 weeks gestation 7. 32 weeks gestation 8. Cesarean delivery 1 2 3 4 5 6 7 8 1. 1,000 g birth weight 2. 2,500 g birth weight 3. 4,000 g birth weight 4. Intensive care nursery 5. Umbilical artery blood ph < 7.0 6. RDS (ventilator therapy > 24 hours) 7. Major malformations 8. Perinatal mortality (per 1,000) Casey et al Obstet Gynecol 107:337, 2006 0

Case 4

A 27 year old woman with Graves hyperthyroidism is planning a pregnancy. She has been on methimazole for 9 months; her current dose is 5 mg/day. She is currently asymptomatic. Menses are regular. She has a 25 gm thyroid gland without nodules. No tremor. Heat rate 88 bpm. Current labs: TSH 0.59 miu/l Free T4 1.7 ng/dl (ref range 0.7-1.9) T3 156 ng/dl (ref range 80-180) TSI 190% (ref range <130)

What should you recommend? A. Thyroidectomy B. Radioactive iodine treatment C. Change now from methimazole to PTU D. Change from methimazole to PTU as soon as pregnancy is diagnosed E. Discontinue anti-thyroid drug as soon as pregnancy is diagnosed

ATD and Birth Defects in a Danish National Registry n = 817,073 Andersen SL et al. J Clin Endocrinol Metab 2013;98:4373-81

Advantages and Disadvantages of Therapeutic Options for Women with Graves' Disease Seeking Pregnancy Alexander EK, Pearce EN, et al. Thyroid 2017;27:315-89

Case 5

A 26 yo woman presents for routine antenatal care at 8 weeks gestation. This is her first pregnancy. She feels well apart from some fatigue and mild nausea. She has no history of thyroid disease. What thyroid testing would you order? A. None B. TSH C. TSH and free T4 D. TSH, free T4, and TPO antibody

Screening for Thyroid Dysfunction in Pregnancy Worldwide opinions and guidelines Group American College of Obstetrics and Gynecology 2002 Endocrine Society 2007 ATA 2011 Endocrine Society 2012 ETA 2015 Recommendation test only for symptoms or known history selective testing of high-risk women selective testing of high-risk women universal screening vs aggressive case finding majority support universal screening Spanish Society of Endocrinology and Nutrition Indian Thyroid Society Indian National Guidelines China universal screening universal screening selective testing of high-risk women universal screening

ATA Guideline 2017 There is insufficient evidence to recommend for or against universal screening for abnormal TSH concentrations in early pregnancy. (No recommendation; Insufficient evidence) There is insufficient evidence to recommend for or against universal screening for abnormal TSH concentrations preconception, with the exception of women planning assisted reproduction. (No recommendation; Insufficient evidence) Universal screening to detect low free thyroxine concentrations in pregnant women is not recommended. (Weak recommendation; moderate-quality evidence) Alexander EK, Pearce EN, et al. Thyroid 2017;27(3):315-389

ATA Guideline 2017 All patients seeking pregnancy, or newly pregnant, should undergo clinical evaluation. If any of the following risk factors are identified, testing for serum TSH is recommended as soon as pregnancy is confirmed. (Strong recommendation, moderate-quality evidence) Alexander EK, Pearce EN, et al. Thyroid 2017;27(3):315-389

High Risk for Thyroid Dysfunction in Pregnancy 1. History of hypothyroidism/hyperthyroidism or current symptoms/signs of thyroid dysfunction 2. Known thyroid antibody positivity or presence of a goiter 3. History of head or neck radiation or prior thyroid surgery 4. Age >30 years 5. Type 1 diabetes or other autoimmune disorders 6. History of miscarriage, preterm delivery, or infertility 7. Multiple prior pregnancies ( 2) 8. Family history of autoimmune thyroid disease or thyroid dysfunction 9. Morbid obesity (BMI 40 kg/m2) 10. Use of amiodarone or lithium, or recent administration of iodinated radiologic contrast 11. Residing in an area of known moderate to severe iodine insufficiency

Case 6

A 23 year old woman presents at at 8 weeks gestation. She has previously miscarried twice. She is feeling well. She has no history of thyroid disease. The thyroid is 25 gm and firm. Labs obtained by her obstetrician include: TSH 2.4 miu/l TPO Antibody >1000 IU/mL (ref range <35) What do you recommend? A. No treatment B. Levothyroxine 50 µg daily C. Selenium 200 mg daily

Association between Thyroid Autoantibodies and Miscarriage in Case-control Studies Thangaratinam S et al. BMJ 2011;342:bmj.d2616

Association between Thyroid Autoantibodies and Preterm Births Thangaratinam S et al. BMJ 2011;342:bmj.d2616

L-T4 Treatment of TPOAb+ Pregnant Women 16 14 12 10 8 75% Risk reduction Miscarriage Preterm Delivery * ** * ** 13.8 69% Risk reduction % % 22.4 25 20 15 6 4 2 3.5 0 TPOAb+ no L-T4 Rx. control (no TPOAb) 2.4 TPOAb+ treated with L-T4 10 8.2 7.0 5 0 * p < 0.05 ** p < 0.01 Negro et al. JCEM 2006;91:2587-91

RCT: LT4 Treatment for TPO+ Women with TSH 10 Enrolled 11 weeks gestation p=0.02 In sensitivity analyses, differences only in women with TSH 4mIU/L p<0.05 No differences: Miscarriage Placental abruption Stillbirth Birthweight Head circumference TPO+/LT4 TPO+/no tx TPOn=65 n=66 n=1028 Nzazrpour S et al. Eur J Endocrinol 2017; 176:253-65

Ongoing trials: The TABLET trial - in the UK - randomizing euthyroid, TPO Ab positive women with a history of infertility or miscarriage to either levothyroxine vs. placebo - Outcome: live birth rates The T4Life trial - in the Netherlands - Randomizing euthyroid, TPO Ab positive women with a history of recurrent miscarriage to LT4 vs. placebo before conception. - Outcome: live birth rates >24 weeks gestation http://www.birmingham.ac.uk/research/activity/mds/trials/bctu/trials/womens/tablet/index.aspx http://www.trialregister.nl/trialreg/admin/rctview.asp?tc=3364

ATA Guideline 2017 There is insufficient evidence to conclusively determine whether levothyroxine therapy decreases miscarriage risk in TPO Ab positive, euthyroid women. However, administration of levothyroxine to TPO Ab positive, euthyroid women with a prior history of miscarriage may be considered given its potential benefits in comparison to its minimal risk. In such cases, 50 μg of levothyroxine is a typical starting dose. (Weak recommendation; Low-quality evidence) Alexander EK, Pearce EN, et al. Thyroid 2017;27(3):315-389

Selenium and the Thyroid in Pregnancy Two Conflicting RCTs:. 200 mg selenium daily decreased postpartum thyroid dysfunction and lowered TPO Ab concentrations during gestation 60 mg selenium daily did not affect TPO concentrations or TPO positivity in pregnant women Patients treated with selenium may be at higher risk for developing type 2 diabetes mellitus. Negro et al. J Clin Endocrinol Metab 2007;92:1263 1268; Mao J et al. Eur J Nutr 2016;55:55 61; Stranges S et al. Ann Intern Med 147:217 223.

ATA Guideline 2017 Selenium supplementation is not recommended for the treatment of TPOAb-positive women during pregnancy. Weak recommendation, moderate-quality evidence. Alexander EK, Pearce EN, et al. Thyroid 2017;27(3):315-389

Case 7

A 32 yo woman is found to have a palpable left 2cm thyroid nodule at 13 weeks gestation. No family history of thyroid cancer, no history of radiation exposure. TSH 0.6 miu/l. left 1.5 x 1.5 x 2.4 cm Spongiform right 0.9 x 1.0 x 1.3 cm Hypoechoic, solid, irregular microlobulated border, microcalcifications NO abnormal cervical lymph nodes

What is the best next step? A. Biopsy left (spongiform) 1.5 cm nodule now B. Biopsy right (hypoechoic) 1.3 cm nodule now C. Defer FNA biopsy until after delivery

ATA 2017 Guideline Thyroid nodule FNA is generally recommended for newly detected nodules in pregnant women with a non-suppressed TSH. Determination of which nodules require FNA should be based upon the nodule s sonographic pattern. The timing of FNA, whether during gestation or early postpartum, may be influenced by the clinical assessment of cancer risk, or by patient preference. (Strong recommendation, Moderate-quality evidence) Alexander EK, Pearce EN, et al. Thyroid 2017;27(3):315-389

The patient elects to undergo FNA biopsy at 14 weeks. Cytopathology from her right nodule is read as Bethesda V (suspicious for papillary cancer). What is the next best step? A. Repeat FNA biopsy with molecular markers B. Thyroid surgery in the second trimester C. Defer thyroid surgery until after delivery

Does pregnancy impact prognosis of newly diagnosed PTC? 3 retrospective studies have shown no differences in recurrence or survival rates in women diagnosed during pregnancy or within 1 year postpartum compared to nonpregnant women 2 recent reports of higher persistence/recurrent disease based upon either Tg, rising Tg Ab or structural neck disease Small numbers of patients Classification of recurrence Recurrence rates of cancer DX during pregnancy discrepant between studies: 60% (Messuti) vs. 10% (Vanucchi) Herzon Arch Otolaryngol Head Neck Surg 1994:120:1191; Moosa J Clin Endocrinol Metab 1997;82:2862; Yasmeen Int J Gynaecol Obstet 2005;91:15; Vannucchi Eur J Endocrinol 2010;162:145; Messuti Eur J Endocrinol 2014;170: 659;

ATA 2017 Guideline PTC detected in early pregnancy should be monitored sonographically. If it grows substantially before 24-26 weeks gestation, or if cytologically malignant cervical lymph nodes are present, surgery should be considered during pregnancy. However, if the disease remains stable by midgestation, or if it is diagnosed in the second half of pregnancy, surgery may be deferred until after delivery. Weak recommendation, Low-quality evidence Alexander EK, Pearce EN, et al. Thyroid 2017;27(3):315-389

Questions?