Lecture title Name Family name Country
Nguyen Thy Khue, MD, PhD Department of Endocrinology HCMC University of Medicine and Pharmacy, MEDIC Clinic Hochiminh City, Viet Nam Provided no information regarding significant relationship with commercial supporters and/or discussion of investigational or non-emea/fda approved (offlabel) uses of drugs as of 4 April 2017
Thyroid disorders and pregnancy
Objectives Physiology of Thyroid function during pregnancy Timing and modality of thyroid screening during pregnancy Dysthyroidism during pregnancy and management
Prevalence of Thyroid Disorders in Pregnancy 0.1-0.2% develop thyrotoxicosis 1-2% already on levothyroxine replacement 2-3% healthy non pregnant women of childbearing age: high TSH 6-10% have TPO antibodies 50% with TPO: postpartum thyroid disease Lazarus Thyroid 2002-ATA 2017 5
The fetal Thyroid Begins concentrating iodine at 10-12 weeks Controlled by pituitary TSH by approximately 20 weeks Burrow GN et al NEJM 1994 6
Physiologic Changes in Thyroid Function During Pregnancy Thyroid binding globulin (TBG) increases TSH levels decrease in early pregnancy Plasma iodide levels decrease due to fetal iodide use and increased maternal clearance -> leads to notable increase in gland size in 15% of women (without abnormal TFTs) Immune tolerance 7
Recommendation of Iodine supplementation during pregnancy WHO 250 g/d for pregnant and lactating women US: 150-290 g/day 150 g/d for women planning to be pregnant 220 g/d for pregnant women 290 g/d for breastfeeding women > 500 g/d should be avoided
Adverse fetal and maternal outcomes associated with maternal thyroid dysfunction Overt Hypothyroidism Subclinical hypothyroidism Isolated hypothyroxinemia Overt hyperthyroidism Fetal outcomes Preterm delivery Low birth weight Miscarriage Prematurity Fetal and neonatal death Neuropsychologi cal impairment * (*inconclusive) Low birth weight Neuropsychologi -cal impairment Preterm delivery Intrauterine growth restriction Congenital malformations Fetal death Maternal outcomes Anemia Placental abruption Postpartum hemorrhage Gestational hypertension Gestational diabetes Pre-ecclampsia Premature rupture of membranes Placental abruption Pre-ecclampsia Gestational hypertension Cardiac failure Thyroid storm 9
Indication Thyroid function testing in Pregnancy Current thyroid therapy Family Hx of autoimmune thyroid disease Goiter History of Other autoimmune disease TPOAb+ Miscarriage Infertility Morbid obesity >30 years High dose neck irradiation Post partum Thyroid dysfunction Therapy for hyperthyroidism Type 1 diabetes mellitus Thyroid 2011, JCEM 97(8):2543, 10
Reference range of TSH during pregnancy TSH reference range (mui/ml) 1 st trimester Second trimester Third trimester American Endocrine Society American Thyroid Association 0.1-2.5 0.2-3.0 0.3-3.0 European Thyroid Association <2.5 <3.0 <3.5
Trimester - specific TSH ranges Negro and Stagnaro-Green BMJ 349:g4929,2014 Or TSH> 4mUI/L 12
Free T4 Useful in pregnant women when trying to distinguish between overt and subclinical thyroid diseases Need regional reference range Clinical decision on diagnosis and treatment of hypothyroidism or hyperthyroidism should mostly be based on serum TSH concentrations and overall clinical picture and symptoms 13
Case 30 yo women, 10 weeks pregnant, had a routine TSH level of 5 mui/l and FT4 1 ng/dl Is this TSH normal? 14
Hypothyroidism and pregnancy 2-3% in pregnant women Overt hypothyroidism: TSH elevated, FT4 decreased (compared to trimester specific range) TSH>10 mui/l irrespective of FT4 levels Subclinical hypothyroidism: TSH elevated but <10, FT4 normal
Common causes of hypothyroidism Hashimoto Thyroiditis Post ablation: surgical, radioactive iodine Medications that alter the absorption or metabolism of levothyroxine Central defects that inhibit the hypothalamic pituitary-thyroid axis
Adjustment of Thyroxine dosage in hypothyroid women during pregnancy Already on Thyroxine: TSH >2.5 miu/l, increase dose by about 30% Newly Diagnosed hypothyroidism: TSH 2.5-5 miu/l-begin 50 g/day TSH 5-8 miu/l -begin 75 g/day TSH > 8mIU/L begin full replacement dose based on weight Monitor TSH every 4 week to 16-20 weeks of gestation, then once between 26-32 weeks After delivery, stop or titrate down levothyroxine, repeat TSH in 4-8weeks Negro and Stagnaro BMJ 349:g4929, 2014
Levothyroxine therapy in subclinical hypothyroidism/pregnancy Levothyroxine is recommended for TPO (+) with TSH greater than pregnancy specific reference range TPO(-) with TSH >10 mui/l Levothyroxine may be considered for: Anti TPO (+) with TSH>2.5 mui/l and below the upper limit of ref range Anti TPO (-) with TSH >ref range and <10mUI/L Levothyorxine is not recommended for pregnant women with anti TPO (-) and TSH <4 mui/l ATA GD 2017
Case 28 yo woman, 08 weeks pregnant, primigravida, nausea, vomiting, 1 kg weight loss in the past 4 weeks TSH 0.01 mui/l FT4 1.90 ng/dl (0.8-1.75) Thyroid gland slightly enlarged, no bruit
Hyperthyroidism and pregnancy 0.4-1.7 % of pregnancy Most common cause Graves disease (85%) Other causes: Transient gestational thyrotoxicosis Hyperemesis gravidarum Toxic nodule Toxic multi-nodular goitre Sub-acute thyroiditis Molar pregnancy 20
Hyperemesis Gravidarum/transient gestational thyrotoxicosis 1-3% of all pregnancies Nausea, vomiting & weight loss+/- ketonuria Often clinically euthyroid Raised FT4, low TSH, raised hcg Severity correlates with hcg & FT4 Usually resolves by 18-20 wk gestation Supportive management 21
Hyperthyroid manifestations / Graves disease Nonspecific symptoms; Tachycardia Heat intolerance Increased perspiration Additional symptoms: Anxiety Hand tremor Weight loss despite a normal or increased appetite 22
Specific findings of Graves disease Goiter with bruit, hyper-vascularity on ultrasound Ophthalmopathy Positive TRAb,TSI Normal Hyper-vascularity of the thyroid 23
Management of Graves disease Anti-thyroid drug: the treatment of choice PTU or Carbimazole Lowest possible dose Regular thyroid function monitoring Beta-blockers for symptom control Some may need thyroid surgery Radio-iodine is contra-indicated 24
PTU vs Carbimazole (Methimazole) PTU partially blocks T4 to T3 conversion Faster control of thyrotoxicosis Difference in placental transfer In vitro study, no difference in placental transfer ATD safe in lactating women PTU up to 750 mg daily or Carbimazole 20-30 mg/d: had no significant effect on infant s thyroid function But propylthiouracil may cause elevated liver enzymes 25
Association of antithyroid drugs (ATD) with congenital anomalies Aplasia cutis Yoshihara et al JCEM 97: 2396, 2012
Face and neck region and urinary system birth defects in ATD exposed Mothers-Registry in Denmark PTU MMI PTU and MMI No ATD in pregnancy Non exposed Children (n) 564 1097 159 3543 811,730 Face and Neck defect Urinary tract defect 5 (0.89%) 0 2 (1.26%) 6 (0.17%) 1,557 (0.19%) 6 (1.06%) 9(0.82%) 1 (0.63%) 15 (0.42%) 3,151 (0.39%) Face and neck region: preauricular and branchial sinus/fistula/cyst Urinary system: single cyst of kidney and hydronephrosis Hazard ration in children exposed to PTU only: Birth defect in the face and neck region was 4.92 (95%CI 2.04-11.86) Birth defect in the urinary system 2.73 (1.22-6.07) Andersen et al J Clin Endocrinol Metab 2013,.98:4373 4381.
Recommendations for Management of Maternal Hyperthyroidism in Pregnancy No recommendation for treatment of subclinical hyperthyroidism (TSH suppressed, normal range FT4 for pregnancy) When treatment required, use PTU in first trimester, then switch to Methimazole in 2 nd and 3 rd trimester to reduce the risk of liver damage Titrate antithyroid drug (ATD) to upper limit of normal or to a T4 range approximately 1.5 upper limit of normal, a suppressed TSH is acceptable Only use ATD in the first trimester when clearly indicated clinically, and use the minimum amount to treat the hyperthyroidism in the mother ATA GD 2017 28
Neonatal Thyrotoxicosis Due to placental transfer of TSHR-Ab May not be apparent until 7-10 days old Irritability, tachycardia, low birth weight, goitre, exophthalmos, jaundice, cardiac failure Raised FT4, positive TSHR-Ab Usually self-limiting, but may need propranolol or Carbimazole 29
Postpartum thyrotoxicosis Prevelence: 1-17% more common in T1D, family history of hypothyroidism, anti TPO (+) euthyroid pregnant women Usually happened within 12 months post partum, mostly between 3-4 m post partum Classical manifestation: transient thyrotoxicosis followed by transient hypothyroidism (5% permanent hypothyroidism) before returning to the eu-thyroid state Differential diagnosis: most difficult with exacerbation of Graves disease Radioactive iodine or technetium uptake test: limited Sonography: PPT hypoechognecity, reduced flow on echo Doppler GD: hypoechogenicity+ hypervascularity on echo Doppler 30
Postpartum thyroiditis Management: based mostly on the degree of clinical symptoms Thyrotoxic phase: Beta-blockers Hypothyroid phase: treatment indicated only if persistent or symptomatic. TFT are useful in guiding decisions Close FU: test TSH, FT4 annually and even in the PP period of future pregnancy (recurrence 70%) 31
Summary Overt hyper and hypothyroidism in pregnancy could have adverse effects on the mother and the baby Early diagnosis and appropriate management is essential to good outcomes Subclinical hypothyroidism should be treated with levothyroxine especially in women with Anti TPO (+) 32
Summary Subclinical hyperthyroidism usually does not required treatment (carefully consider the presence of transient gestational thyrotoxicosis) To date, there is insufficient data to prove that levothyroxine supplementation in euthyroid pregnant women with Anti TPO (+) could be beneficial for the mother and the baby. 33
Thank you for your attention