Thyroid disorders in pregnancy Dr.K.Saravanan ECG & ECHO Club of Trichy

Control of thyroid function

Thyroid Disorders & Pregnancy Specific to Pregnancy : Transient hyperthyroidism of HG Postpartum thyroiditis Neonatal & fetal hyperthyroidism Neonatal & fetal hypothyroidism Not specific to Pregnancy : Thyrotoxicosis , Hypothyroidism Thyroid nodules , Thyroid neoplasia

Physiological adaptation in pregnancy

Clinical presentation - 1 A 19 year old primi with H/o 54 days amenorrhea was referred by obstetrician with C/o palpitations, weight loss of 2-3 months duration (8 kg), Her haemoglobin was 9.8 g/dl, HR  120/mt with prominent eye sign.

Q1 In a background of clinical suspicion of Graves disease, the preferred investigation of choice : TSH, T3, T4 TSH, FT4, FT3 TSH, FT4 4. TSH, FT4, Anti-TPO antibodies

Thyroid Function Tests in Pregnancy-hyperthyroidism TSH Low FT4 Normal High Hyper thyroidism FT3 Subclinical Hyperthyroidism Normal

Q2 Her TSH was < 0.001 (n 0.3-4.5 mIU/L)and FT4- 8.9 (n 0.932-1.71 ng/dl). Her TPO antibodies were positive. Drug of choice is Propanolol + Carbimazole Methimazole PTU

TSH  low FT4 ,FT3normal Subclinical hyperthyroidismobserve FT4  high Clinical  hyperemesis Observe , fluid therapy TSH  low FT4  high Clinical  thyrotoxicosis Anti-TPO antibodies +ve Treat with PTU TSH  low FT4 ,FT3normal Subclinical hyperthyroidismobserve

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

Hyperthyroidism & Pregnancy Useful Physical Signs : Inappropriately low weight gain for gest. age Goiter Lid lag Muscle weakness Heart rate >100 Onycholysis

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

Approach in Pregnant & Suppressed TSH Recheck in 5 wks FT4, FT3, T4, T3 Thyroid Ab’s Examine Still suppressed 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)

Thyrotoxicosis & Pregnancy: Rx No RAI ever (destroy fetal thyroid) PTU Start 100 mg tid, titrate to lowest possible dose Monitor dose by: FT4, TSH TSH alone is less useful (lags, hCG suppression) Aim for high-normal to slightly elevated hormone levels FT4 0.85-1.9 ng/dl and TSH 0.5 – 2.5mIU/L 3rd trimester: titrate PTU down & decrease prior to delivery if TFT’s permit Consider fetal U/S wk 28-30 to R/O fetal goitre If allergy/neutropenia on PTU: 2nd trimester thyroidectomy Propranolol

TO summarize…. Arrive at the diagnosis. Correlate clinically Rule out hyperemesis Treat with PTU and propranolol in hyperthyroidism Watch for neutropenia and infections Monitor FT4 to assess control

Points to ponder……. Target FT4 is 0.85-1.9 ng/dl TSH alone not helpful in monitoring PTU dose. PTU dose adjusted every 3-4 weeks. Symptoms improve in 3-4 wk but full response only after 8 weeks. Block and replace therapy avoided in pregnancy due to risk to fetus. Fetal monitoring is important Subclinical hyperthyroidism-no intervention .

Q4 Clinical Presentation - 2 Known hypothyroidism on 150 mcg Eltroxin with H/o 3 months amenorrhea comes with TSH,T3,T4 results. TSH-2.5(n 0.3 – 4.5 mIU/L) T4 – 16.4 (n 5.13-14.06 ug/dl) T3 – 3.2 (n 0.84-2.02 ng/dl). Eltroxin should be stopped. Eltroxin dose should be increased in pregnancy Check FT4 alone Check FT4 ,FT3

Thyroid Function Tests in Pregnancy-hypothyroidism TSH High FT4 Normal Low Subclinical Hypothyroidism Primary Hypothyroidism

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):549-555, Aug 31, 2001): Cognitive testing of children age 7-9 Untreated hypothyroid mothers vs. normal mothers: Average of 7 IQ points less in children Increased risk of IQ < 85 (19% vs. 5%)

Causes & Diagnosis of Hypothyroidism Hashimoto’s (chronic thyroiditis; most common in developed countries) & iodine deficiency -> both associated with goiter Subacute thyroiditis -> not associated with goiter Thyroidectomy, radioactive iodine treatment Iodine deficiency (most common worldwide; rare in US)

Symptoms Fatigue Constipation Cold intolerance Weight gain Muscle cramps CTS Insomnia , lethargy

Points to ponder ….. Known hypothyroid, eltroxin is increased by 30-50% in first trimester. First time diagnosed start eltroxin at 1-2 mcg/kg /day Target TSH is 0.5 – 2.5mU/L TSH checked initially at 4-6 weeks and later 8 weeks Space eltroxin and vitamin tablets to avoid interaction. Postpartum-dose is reduced Recommended iodide salt avg 250 mcg/day

Q5 Clinical Presentation - 3 27 year old female and 3 MA with clinical features suggestive of hypothyroidism has a TSH  6.8 and FT4  1.2 ng. This is Overt Hypothyroidism Subclinical Hypothyroidism Subacute Thyroiditis Overt Hyperthyroidism

Recommended approach in this patient Q6 Recommended approach in this patient Start eltroxin Repeat TSH every 4 weeks until 16-20 weeks and atleast once between 26-32 weeks Repeat TSH & FT4 every 4 weeks until 16-20 weeks and atleast once between 26-32 weeks No Intervention at all.

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: 2.5-5.0 mU/L: recheck TSH during 1st trimester 0.4-2.5 mU/L: do not need to recheck during preg If TSH not done preconception do at earliest prenatal visit: 0.1-0.4 mU/L: hCG effect (9% preg), recheck in 5wk < 0.1 mU/L: recheck immediately with FT4, FT3, T4, T3

Takeaways…….. Thyroid is second commonest endocrine disorder in pregnancy. Untreated hypothyroidism-fetus more affected Untreated hyperthyroidism-mother more affected Subclinical hypothyroidism- treat Subclinical hyperthyroidism-followup Routine screening- not recommended

Management….. LT4  1-2 mcg/kg/day Dose adjustments by 25-50 mcg

Hyperthyroidism & Pregnancy TPO antibodies are increased in (80–90%) of patients with Graves disease + Other autoimmune disorders (TRAbs) are increased in >80% of patients with Graves disease

Endo consult FT3, rT3 MRI, α-SU TSH Low High FT4 & FT3 FT4 Low High Central Hypothyroid 1° Thyrotoxicosis 1° Hypothyroid If equivocal 2° thyrotoxicosis RAIU TRH Stim. Endo consult FT3, rT3 MRI, α-SU MRI, etc.

EFFECTS OF PREGNANCY ON THYROID PHYSIOLOGY Physiologic Change Thyroid-Related Consequences ↑ Serum thyroxine-binding globulin ↑ Total T4 and T3; ↑ T4 production ↑ Plasma volume ↑ T4 and T3 pool size; ↑ T4 production; ↑ cardiac output D3 expression in placenta and (?) uterus ↑ T4 production First trimester ↑ in hCG ↑ Free T4; ↓ basal thyrotropin; ↑ T4 production ↑ Renal I- clearance ↑ Iodine requirements ↑ T4 production; fetal T4 synthesis during second and third trimesters   ↑ Oxygen consumption by fetoplacental unit, gravid uterus, and mother ↑ Basal metabolic rate; ↑ cardiac output

Thyroid function in mother and foetus

No TSH & FTI at end of 1st 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

6. Women with type I diabetes. 7. Women with other autoimmune disorders. 8. Women with infertility who should have screening with TSH as part of their infertility work-up. 9. Women with previous therapeutic head or neck irradiation. 10. Women with a history of miscarriage or preterm delivery.

Why treat hypothyroidism in preg? To prevent: Premature birth LBW Abruption,PPH Impaired neuropsychological development in child

Physiologic thyroid adaptations in pregnancy TBG FT4, FT3 hCG TSH Plasma iodide

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?

Hyperthyroidism & Pregnancy Complications First-trimester spontaneous abortions. High rates of still births and neonatal deaths. low birth weight infants : ↑ 2-3 folds. Premature delivery. Fetal or neonatal hyperthyroidism. Intrauterine growth retardation .

Case Presentation - 2 A 19 year old primi with H/o 54 days amenorrhea was referred by obstetrician for C/o palpitations, weight loss of 2-3 months duration (8 kg), Her hemaglobin was 9.8 g/dl, HR  120/mt with prominent eye sign.

Q1 In a background of clinical suspicion of Graves disease, the preferred investigation of choice : TSH, T3, T4 TSH, FT4, FT3 TSH, FT4 TSH, Anti-TPO antibodies

Q2 Her TSH was < 0.001 and FT4 8.9. Her TPO antibodies were positive. Drug of choice: Carbimazole Methimazole Betablockers PTU

Q3 Restart LT4 in preconception dose Wait for 4 weeks and recheck TSH Known hypothyroidism on 150 kg LT4 lost following and came 2 years later with H/o 3 months amenorrhea. She had stopped LT4 since conception and has checked TSH now which was 2.8 Restart LT4 in preconception dose Wait for 4 weeks and recheck TSH Restart LT4 in low dose Wait till delivery and then restart LT4

The Fetal Thyroid Begins concentrating iodine at 10-12 weeks Controlled by pituitary TSH by approximately 20 weeks

10-12 wks of gestation: Fetal thyroid concentrates iodine, synthesize T3 and T4. The fetal pituitary differentiates. Prior to 12 weeks the mother is the sole source of thyroid hormone to the fetus. Fetal thyroid function is at low basal level till 18-20 wks At birth TSH 70uU/ml. Day 2max. TSH 12uU/ml

Treatment indicated if FT4>2.0ng/dl PTU 50-100mg q12 hours in pt. with minimal symptoms (doses>200 mg of PTU can result in fetal goiter & Hypothyroidism Pt with large goiters & long disease duration may require larger initial doses 100-150mg tid Clinical improvement (weight gain & ↓in HR) is noted in the first 2-6 wks, with FT4 improvement in the first 2 wks Once clinical improvement occurs the dose of PTU is ↓by half. Goal to keep FT4 at the upper limit of normal, with least amt of medication In 30% of pt PTU may be D/C’ed in the last 4 - 8wks of pregnancy (Mestman. Best Practice & Research clin endoMetb.,200,vol 18,no. 2,27-88)

CENTRAL CONGENITAL HYPOTHYROIDISM Uncontrolled maternal hyperthyroidism High levels of serum T4 in maternal circulation cross placental barrier Feed back to the fetal pituitary with suppression of fetal pituitary TSH Diagnosis : Neonatal serum FT4 is low & serum TSH is low normal or inappropriate for the level of FT4. In majority of infants there is a return to euthyroidism in a few weeks to months. Rx with LT4 and long term follow up

Physiologic Changes in Thyroid Function During Pregnancy Maternal Status TSH **initial screening test** Free T4 Free Thyroxine Index (FTI) Total T4 Total T3 Resin Triiodo-thyronine Uptake (RT3U) Pregnancy No change Increase Decrease Hyperthyroidism Increase or no change Hypothyroidism Decrease or no change

Physiologic adaptation during pregnancy increase in thyroid-binding globulin secondary to an estrogenic stimulation of TBG synthesis and reduced hepatic clearance of TBG ;two to threefold levels of bound proteins, total thyroxine, and total triiodothyronine are increased and resin triiodothyronine uptake (RT3U) is decreased begins early in the first trimester, plateaus during midgestation, and persists until shortly after delivery decrease in its hepatic clearance,estrogen-induced sialylation free T4 and T3 increase slightly during the first trimester in response to elevated hCG. decline to nadir in third trimester

human chorionic gonadotropin (hCG) intrinsic thyrotropic activity begins shortly after conception, peaks around gestational week 10,declines to a nadir by about week 20 directly activate the TSH receptor partial inhibition of the pituitary gland (by cross-reactivity of the α subunit) transient decrease in TSH between Weeks 8 and 14 mirrors the peak in hCG concentrations 20% of normal women, TSH levels decrease to less than the lower limit of normal

Graves' hyperthyroidism occurs in approximately 0 Graves' hyperthyroidism occurs in approximately 0.2 percent of women, and it occurs in approximately one to five percent of infants born to these mothers [2-4].

Hyperthyroidism & Pregnancy Causes Graves disease (85–90% of all cases) Sub-acute thyroiditis Toxic MNG Toxic adenoma TSH-dependent thyrotoxicosis Iodine-induced hyperthyroidism Exogenous T3 or T4

Management TSH >2.5  monitor Target TSH  0.5—2.5 Always check FT4 TPO antibodies if TSH is 3-10 TSH to be checked every 8 weeks LT4  1-2 mcg/kg/day Dose adjustments by 25-50 mcg

Neonatal Grave’s Rare, 1 - 5% 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 2nd 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 Present @ 3-6 mos 20% mortality, persistent brain dysfunction Screen for fetal goiter even in mothers treated previously with RAI or ATD before consumption.

Pregnancy: screen for thyroid dysfn ? Universal screening not currently recommended: ACOG, AACE, Endo Society, ATA Controversial ! Definitely screen: Goitre, Family H/o thyroid dysfn., prior postpartum thyroiditis, T1DM Ideally, check TSH preconception: 2.5-5.0 mU/L: recheck TSH during 1st trimester 0.4-2.5 mU/L: do not need to recheck during preg If TSH not done preconception do at earliest prenatal visit: 0.1-0.4 mU/L: hCG effect (9% preg), recheck in 5wk < 0.1 mU/L: recheck immediately with FT4, FT3, T4, T3

8. SCREENING FOR THYROID DYSFUNCTION DURING PREGNANCY 1. Women with a history of hyperthyroid or hypothyroid disease, PPT, or thyroid lobectomy. 2. Women with a family history of thyroid disease. 3. Women with a goiter. 4. Women with thyroid antibodies (when known). 5. Women with symptoms or clinical signs suggestive of thyroid underfunction or overfunction, including anemia,elevated cholesterol, and hyponatremia.

Hyperthyroidism & Pregnancy TPO antibodies are increased in (80–90%) of patients with Graves disease + Other autoimmune disorders (TRAbs) are increased in >80% of patients with Graves disease