6/9/2016 DISCLOSURES THYROID DISEASE IN PREGNANCY: • I have nothing to disclose IS IT INCREASING? Antepartum and Intrapartum Management Conference June 9, 2016 Lena H. Kim, MD UCSF Assistant Clinical Professor, MFM OBJECTIVES THYROID PHYSIOLOGY • Review thyroid physiology in pregnancy • Thyroid gland – Metabolism, growth, cognition, cardiovascular • Define thyroid pathophysiology • Thyroxin (T4) – Hypothyroidism • Triiodothyronine (T3) • Subclinical hypothyroidism – Calcium homeostasis – Hyperthyroidism • Calcitonin • Outline pregnancy management Ain et al. Endocrinol Metab 1987;65:689 1
6/9/2016 TRIMESTER SPECIFIC TSH (mIU/L) THYROID CHANGES IN PREGNANCY NORMAL REFERENCE RANGES • Increased thyroxine-binding globulin (TBG) – Estrogen � 2x increase TBG Trimester Lower limit Upper limit – Increased serum total T4 & total T3 • TSH-receptor stimulated by hCG 1 0.1 2.5 – Common alpha subunits 2 0.2 3.0 – Homology between beta subunits 3 0.3 3.0 – 10-20% pregnancies subclinical hyperthyroidism • Transiently low or undetectable TSH in the 1 st trimester Dashe et al. Obstet Gynecol 2005;106:753 Glinoer D. Endocr Rev 1997;18:404 THYROID LAB ISSUES IN PREGNANCY IODINE NEEDS IN PREGNANCY • Higher iodine needs in pregnancy • Free T4 assay may not be reliable – Increased thyroxine (T4) production • Serum total T4 & T3 in pregnancy • IOM 2006 – 1.5X higher than non-pregnant women – 220 mcg pregnancy – 290 mcg lactation – TBG excess • ATA 2011 – 150 mcg in prenatal vitamins • Excessive iodine detrimental – Fetal hypothyroidism � fetal goiter – Upper limit of benign intake 600-1100 mcg daily Stagnaro-Green et al. Thyroid 2001;21(10):1081 Lee et al. Am J Obstet Gynecol 2009;200:260.e1 2
6/9/2016 GOITER IN PREGNANCY FETAL THYROID • Fetal TSH production begins @10-12 wks • 10-40% thyroid enlargement • Thyroid hormone production @18-20 wks • Increased iodine excretion in urine • Maternal thyroid hormone placental transport • Low risk iodine deficiency in U.S. – Newborns with congenital absence of thyroid • 20-50% thyroid hormone levels of normal newborns – TSH receptor antibodies can cause fetal disease • Both hyper and hypothyroidism – Little Maternal TSH crosses to fetus – TRH can cross the placenta & stimulate fetal TSH Burrow et al. NEJM 1994;331:1072 Rasmussen et al. Am J Obstet Gynecol 1989;160:1216 HYPOTHYROIDISM CLINICAL PICTURE HYPOTHYROIDISM • Globally � iodine deficiency #1 cause • U.S. prevalence 0.1-2.0% – 5Xs greater in women • In the U.S. � Hashimoto’s most common – 0.3-0.5% of screened pregnant women – Chronic autoimmune thyroiditis • Symptoms • Other etiologies – Weight gain – Treated Grave’s – Fatigue – Pituitary or hypothalamus disorders – Constipation • Diagnosis – Cold intolerance – Elevated TSH + decreased FT4 Stagnaro-Green et al. Thyroid 2001;21(10):1081 Stagnaro-Green et al. Thyroid 2001;21(10):1081 3
6/9/2016 HYPOTHYROIDISM PREGNANCY SUBCLINICAL HYPOTHYROIDISM OUTCOMES • Increased risk of adverse pregnancy outcomes • Diagnosis – Infertility – Elevated TSH but normal FT4 – Miscarriage – General population prevalence 4-10% – Preeclampsia – Placental abruption • 2.0-2.5% of screened pregnant women in the U.S. – Preterm delivery • Controversial whether impacts pregnancy – NRFHT – Cesarean – Low birth weight – Postpartum hemorrhage – Child neuropsychological & cognitive impairment Burns et al. Ann Intern Med 2016;164:764 Casey et al. Obstet Gynecol 2006;108:1283 RCT CRITIQUE • Screened and Rx’d too late in GA? • Age 3 too early for neurocognitive testing? • 24% lost to follow up rate too high? • RCT levothyroxine for SCH in pregnancy • More RCTs needed – 22,000 screened women, median 12w3d • NICHD MFMU Network TSH trial pending – TSH 3.8 screened v. 3.2 control – Thyroid therapy for mild thyroid deficiency in pregnancy – 390 LT4 150mcg v. 404 control, median 13w3d Rx – Follow up to age 5 – IQ no different age 3 • Mean IQ 99.2 v. 100.0, IQ <85 12.1% v. 14.1% Lazarus et al. NEJM 2012; 366:493 4
6/9/2016 HYPERTHYROIDISM HYPERTHYROIDISM CLINICAL PICTURE • Diagnosis • Prevalence general population 1.3% – TSH<0.1 mIU/L & elevated FT4 +/- elevated FT3 – More common in women 5:1 • Older women 4-5% – TSH as low as 0.03-0.1 may still be physiologic – Uncommon in pregnancy • Grave’s most common • 0.1-0.4% of all pregnancies – Thyrotropin receptor antibody (TRAb) • Symptoms – Thyroid stimulating immunoglobulins (TSI) – Overlap with pregnancy • hCG mediated • Tachycardia, heat intolerance, increased perspiration – No need to treat – Anxiety • Toxic multinodular goiter – Tremor • Toxic adenoma – Unexplained weight loss • Struma ovarii – Goiter & ophthalmopathy (Grave’s) Krassas Endocr Rev 2010;31:702 Bahn et al. Thyroid 2011;21(6):593 HYPERTHYROIDISM PREGNANCY FETAL THYROID DISEASE OUTCOMES • Pregnant women with Grave’s • Increased risk of adverse pregnancy outcomes – 1-5% newborns hyperthyroid – Miscarriage • Fetal tachycardia – Preeclampsia • Fetal goiter, advanced bone age, craniosynostosis – IUFD • IUGR – IUGR & low birth weight • Hydrops – Trans-placental TSH receptor stimulating Abs – Preterm labor/preterm delivery – Higher risk with higher maternal titers – Maternal CHF – Thyroid storm Weetman AP. NEJM 200;343:1236 Miller et al . Obstet Gynecol 1994;84:946 5
6/9/2016 CONGENITAL HYPOTHYROIDISM THYROID PEROXIDASE ANTIBODIES • Agenesis or dysgenesis of the fetal thyroid • Euthyroid but +TPO Abs – Adverse pregnancy outcomes • Congenital dyshormonogenesis • Miscarriage risk 2-3X higher • Iodine deficiency in endemic areas • Preterm birth 2X higher • Perinatal mortality • Large for gestational age – 20% develop subclinical hypothyroidism Thangaratinam et al. BMJ 2011;342:d2616 POSTPARTUM THYROIDITIS THYROID STORM • Transient hyperthyroidism within 1 year • Life threatening • Prevalence 4.1% • Clinical presentation – 0.2% related to Grave’s disease – Hyperpyrexia: T>103F/39.4C – CV dysfunction: tachycardia, CHF • Sometimes followed by hypothyroidism – Altered mental status – Transient or permanent (rare) – Goiter – Elevated FT4 +/- elevated FT3 + low TSH Amino et al. Endocr J 2000;47:645 ACOG Practice Bulletin 148, April 2015 6
6/9/2016 AUDIENCE QUESTION #1 RISK FACTORS FOR THYROID STORM Do you universally order TSH with 1 st • Long standing untreated hyperthyroidism tri labs? • Precipitated by an acute event 66% A. Yes – Surgery B. No – Trauma – Infection C. Sometimes 22% – Acute iodine load 12% – Irregular or discontinuation of antithyroid Rx – PARTUITION s o s e N e Y m t i e m o S Sheffield et al. AJOG 2004;190:211 UNIVERSAL TSH SCREENING AUDIENCE QUESTION #2 CONTROVERSIAL 34yo G1P0 @12 wks - TSH is 3.5 but FT4 normal • ACOG, ATA and Endocrine Society – Not universal but yes targeted Do you start levothyroxine? • ATA says screen pregnant women if: A. Yes – Age >30 56% – Infertility B. No – Symptoms C. Maybe – counsel patient 1 st – Type I Diabetes 19% 18% – Morbid obesity (BMI ≥ 40 kg/m 2 ) D. Don’t know 7% – History of PTD or recurrent miscarriage – Family or personal history of thyroid disease s o e t w – History of head or neck radiation N s Y 1 o n t n k e t i ’ t n a o p D – From an area where iodine deficiency is endemic e l s n u o c – e b y a M ACOG Practice Bulletin 148 April 2015 7
6/9/2016 ARGUMENTS IN FAVOR OF SCREENING HYPOTHYROIDISM MANAGEMENT • Medication • Risk based TSH screening – Thyroid hormone (T4) replacement – Misses 1/3 rd of women with hypothyroidism – 30-50% increased need in pregnancy • Treatment might increase IQ of offspring • As soon as UPT+ � double dose 2 days a week – Becomes cost-effective? • Lab surveillance – TSH & FT4 every trimester for dose adjustments – TSH & FT4 four weeks after dose adjustment • Fetal surveillance – Usual obstetric care Stagnaro-Green et al. Thyroid 2001;21(10):1081 HYPERTHYROIDISM MANAGEMENT TPO ANTIBODY MANAGEMENT • Medication • Levothyroxine for euthyroid women? – PTU 1 st tri � methimazole 2 nd & 3 rd tri – Not universally screening for TPO Abs – PTU risk of maternal hepatic failure – Methimazole risk of fetal aplasia cutis – Treat if recurrent miscarriage? – Minimal dose needed – Monitor TSH in pregnancy – Beta blockers • Lab surveillance – Goal = upper limit of normal FT4 – Check FT4 every 4 weeks for dose adjustments • Fetal surveillance – 3 rd tri serial growth sonograms + antenatal testing Stagnaro-Green et al. Thyroid 2001;21(10):1081 Negro et al. J Clin Endocrinol Metab 2006;91:2587 8
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