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DR RAJEEV SOOD DR RASHMI VOHRA DEPT. OF O.B.G.

IGMC SHIMLA

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Most common endocrine disorder in pregnancy. 1-2% pregnant women. Pregnancy may modify course of thyroid disease. Pregnancy outcome can depend on optimal management of thyroid disorders.

The Himalayan goiter belt - word’s largest belt from Kashmir to Naga Hills.

Thyroid; derived from Greek word – means shield gland. Highly vascular organ.

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Brownish red, 2 lobes (4x2cm), one isthmus(2x2cm).
30% have pyramidal lobe. Weight: 15-20g

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Hypothalamic-Pituitary axis governs thyroid physiology.
HYPOTHALAMUS

TRH
PITUITARY 3,5,3’,5’ tetra-iodo-L-thyronine (levothyroxine,L-thyroxine,T4)

TSH
THYROID

3,5,3’-tri-iodo-Lthyronine (liothyronine, triiodothyronine;T3)

 iodine

reduced in gut

iodide

transported to

Thyroid

Iodide incorporated into gp thyroglobulin

MIT

DIT

T4 enters circulation by direct glandular secretion.  T3 is produced by mono-deiodination of T4 in periphery.


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T4 bound to circulating transport proteins –
Thyroxine binding globulin (TBG), Thyroxine binding prealbumin or transthyretin, Albumin.

Serum TSH FT4

Units mU/L ng/dl

1st trimester 0.03-2.3 0.86-1.77

2nd 0.03-3.7 0.63-1.29

3rd 0.13-3.4 0.66-1.12

FT3

pmol/L

3-5.7

2.8-4.2

2.4-4.1

ratio FT4:FT3 :: 4:1

 (1)
(2) (3)

Increased thyroxine requirement in pregnancy:
TBG hCG Free thyroid hormones stimulates TSH rp H-P-T axis stimulation

peripheral metabolism.
placental type II deiodinase

?
(fetus is dependent on type II conversion)

T4
pl type III deiodinase

T3
rT3

T4

3,3’diiodothyronine(T2)

PHYSIOLOGIC CHANGE Increased TBG

CLINICAL IMPORTANCE Need for T4 production TT3 & TT4 levels Interference with FT4 assay accuracy T3 & T4 metabolism Need for T4 production

Placental de-iodination of T4

Increased iodine clearance (renal clearance and fetal transfer)
B HCG elevation 1st TM

iodine requirement Risk of maternal and fetal hypothyroidism and goiter
FT4 & TSH Transient mild thyrotoxicosis Graves’ disease improvement Exacerbation of Graves’ disease Precipitation of postpartum thyroiditis

Reduction in TSHRAb during pregnancy Postpartum increase in thyroid antibodies

organization

Thyroid screening with TSH Case finding Case finding

Goal TSH(mIU/L)

Treatment of subclinical hypothyroidism Not recommended Not specified

ACOG oct 2007 USPSTF(United States Preventive Services Task Force) TES(The Endocrine Society) AACE( American Association of Clinical Endocrinologists) BTA(British thyroid association)

Not specified Not specified

Case finding

2.5 in Ist TM 3 in IInd &IIIrd TM 0.3-3.0

Recommended

Routine

Recommended

Case finding

0.4-2.0

Recommended

Sign/symptoms of hypo or hyperthyroidism


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Goiter
h/o hyperthyroid or hypothyroid disease, postpartum thyroiditis or thyroid surgery Previous therapeutic head or neck irradiation Autoimmune disorder Family history of thyroid disease Infertility History of miscarriage or preterm delivery Thyroid antibodies Unexplained anemia or hyponatremia Increased cholesterol level

Events in fetus
Maternal thyroxine in coelomic fluid THR gene expression in human brain Fetal iodine uptake Fetal thyroxine secretion 6 weeks 8 weeks 10-14 weeks 18 weeks

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Hypothyroidism Autoimmune thyroid disease


Hyperthyroidism
Postpartum thyroiditis

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Incidence: 1 - 3 per 1000 pregnancies. Types: Primary - inadequate thyroid hormone production despite pituitary gland stimulation(including iodine deficiency). Central - insufficient stimulation of the thyroid by the pituitary or hypothalamus.

Subclinical – Elevated TSH levels normal FT4 in absence of clinical symptoms.
Overt – increased TSH with low thyroxine levels with clinical symptoms.

PRIMARY HYPOTHYROIDISM
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SECONDARY HYPOTHYROIDISM
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Hashimoto thyroiditis Subacute thyroiditis Endemic iodine deficiency Suppurative thyroiditis Previous thyroidectomy Previous radioablation Medication exposure

Hypothalamic or pituitary tumor Surgery Radiation Sheehan syndrome Lymphocytic hypophysitis

SUBCLINICAL HYPOTHYROIDISM ISOLATED HYPOTHYROXINEMIA

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Lymphadenoid thyroiditis ; chronic lymphocytic thyroiditis. Most common cause in iodine sufficient population. Incidence: 4 per 1000. female: male : 5:1 Antithyroid antibodies damage the gland. Transient hyperthyroidism destroyed) hypothyroidism(90% gland

SUBACUTE GRANULOMATOUS THYROIDITIS
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SUBACUTE LYMPHOCYTIC THYROIDITIS

Subacute painful thyroiditis Viral infection Sudden onset Fever, myalgia, neck pain

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Subacute painless thyroiditis Postpartum thyroiditis Painlessly enlarged thyroid gland.

L/E  Painfully enlarged thyroid

Subacute granulomatous thyroiditis Subacute lymphocytic thyroiditis Transient hyperthyroidism Transient hypothyroidism 90% recover
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10% persistent goiter

Lasts 4-6 weeks; may be 9 months Differentiated from Graves disease by lack of radioiodine uptake on thyroid scan Symptomatic treatment.

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Leading cause of preventable mental retardation worldwide. Mean IQ loss of 13.5 points. Iodine sufficiency determined through measuring median Urinary Iodine excretion. Insufficient urinary iodine: Pregnancy : <150mcg/L Lactation : <100mcg/L renal clearance Iodine needs increase in pregnancy fetal and placental uptake

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Recommended iodine intake (μg/d) Pregnant women Lactating women Children 0-5 years 6 to 12 years 250 250 90 120

Excessive iodine (μg/d)

500 500 180 180

>12 years

150

180

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Iodised salt : 46–76 mg/kg Shrimp (85 grams) : 35mcg Egg, boiled : 12mcg Navy beans, cooked – ½ cup : 32mcg Potato with peel, baked – 1 medium : 60mcg Seaweed (7 grams) dried – 4,500mcg (highest). ?

Iodine should be added after cooking of food.

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Secondary hypothyroidism Pituitary necrosis from vascular hypoperfusion Spectrum varies from failure of lactation or resume menses to acute panhypopituitarism 90% develop secondary hypothyroidism.

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Secondary hypothyroidism Peripartum period Autoimmune disorder Anterior pituitary destruction Panhypopituitarism to single hormone deficiency Imaging: enhancing sella turcica mass Mass effects (headache and visual field changes)

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TSH ; N FT4 & FT3 Prevalence in pregnancy- 2-5% 31% +ve for TPO antibodies. More commonly seen with autoimmune diseases

Associated with gestational hypertension, preterm delivery, stillbirths, abruption.

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N TSH

FT4

Prevalence: 1-2% of pregnancies. No adverse affects on pregnancy outcome No benefit of levothyroxine treatment.

Fatigue,

Insomnia,


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Constipation,
Cold intolerance, Weight gain,


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Periorbital oedema,
Myxedema, Prolonged relaxation of DTRs.


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Carpal tunnel syndrome,
Hair loss, Voice changes,


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Reduced memory; slowed thinking,
Muscle cramps, Dry skin,

Goiter.

ON PREGNANCY  early pregnancy failure,
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ON FETUS  neurodevelopmental delay,
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pre-eclampsia(5-10%), placental abruption(1%), Preterm delivery(10-15%) Malpresentation,

deafness, stunted growth , Peripartum hypoxia and increased risk of neonatal mortality


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low birthweight,
Stillbirth, PPH.

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TSH Low FT4

?
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Low FT4I(4.5-12.5mcg/dl) Antithyroid antibodies (anti-TPO and antithyroglobulin)

Goal

To return thyroid hormone levels to within the reference range. ?

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Euthyroidism at the time of conception. If on treatment- delay pregnancy until TSH is normal.

do not take levothyroxine and multivitamins at the same time (interference with absorption of thyroxine)
adequate iodine intake (250mcg/d). Dietary goitrogens : cabbage, cauliflower, broccoli and even water purifying agents should be avoided. Boiled water is recommended.

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>/=1 risk  factor for thyroid ds

S.TSH

0.08-<3

Euthyroid:no further work up

>/=3

Repeat TSH,FT4, TPO Levothyroxine started TSH>/=3 N FT4, +/- TPO SUBCLINICAL HYPOTHYROIDISM TSH>/=3 Low FT4 +/-TPO

Normal results

HYPOTHYROIDISM

EUTHYROID: Stop levothyroxine

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Levothyroxine sodium - most widely prescribed treatment Safe for both mother and fetus. Category A. Available dosages - 25–300 mcg.

Dose : 30% increase from non pregnant value, if already hypothyroid.
If newly diagnosed in pregnancy : 1.0–2.0 mcg/kg/day or approximately 100 – 150 mcg of levothyroxine daily. TSH measured 4-6 weeks following dose change with TSH goal between 0.5-2.5mIU/L

Once stable, TSH checked every 8 weeks.

Bioavailability affected by medications or food: taken empty stomach. Absorption: Carafate, cholestyramine, ferous sulphate & calcium carbonate. Clearance: phenytoin, carbamazepine. Postpartum: Decrease dose by 30% (diagnosed in pregnancy) Prepregnancy dose (hypothyroid before pregnancy) TSH reassessed 6 week postpartum.

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ON MOTHER
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ON FETUS

Related to Overtreatment hyperthyroidism. transient hair loss. BMD

smaller head circumference and LBW.

Women should be clinically and biochemically euthyroid prior to labor. Obstetric complications including increased risk of stillbirth, preterm delivery, pre-eclampsia and placental abruption should be kept in mind.

Causes:

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Thyroid dysgenesis
Thyroid apasia Thyroid hypoplasia


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Thyroid ectopy
Drug induced (thioamides ,amiodarone , lithium , potassium iodide) Dyshormogenesis


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TSH receptor mutations
Thyorid hormone resistance Pendred’s syndrome: defect in iodine organification and sensorineural deafness.

In utero therapy:

Fetus effectively absorbs T4 from amniotic fluid.
3rd trimester fetal T4 requirement : 6 ug / kg /day. Intraamniotic administration of 250 – 500 ug of thyroxine done at 7 – 10 days interval. In term infants : Requirement : 10 – 15 ug /kg /day. TSH levels kept below 5 mU /l and T4 levels at 10-16 ug /dl. Tab thyroxine crushed and fed directly to the infant.

Thyroid antibodies:
 directed towards cytoplasmic antigensthyroid peroxidase (TPOAb) and  thyroglobulin (TgAb) antibodies.

 directed to the TSH receptor

TSH receptor antibody (TSHRAb).

TPOAB

present in 10-15% normal population.

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Thyroid autoimmunity Causes :

increased miscarriage rates.

subtle maternal thyroid dysfunction autoimmune imbalance; rejection of the fetus thyroid antibodies affecting fetal thyroid gland ; fetal loss Associated increased maternal age

Trophoblast secrete immunosuppressant factors

antibody titers

graves disease improvement
antibody titer post partum

postpartum flare up
postpartum thyroiditis.

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Incidence: 0.1 to 0.4 % Types: Subclinical hyperthyroidism-suppressed TSH, normal FT4 and FT3 Overt-suppressed TSH and elevated FT4 and/or FT3 Gestational- detected in pregnancy.

Intrinsic thyroid disease  Graves’ disease (most common)  Toxic nodule – single or multiple  Subacute or silent thyroiditis Excessive, exogenous thyroid hormone  Factitious  Therapeutic(amiodarone) Gestational thyrotoxicosis  Hyperemesis  Gestational trophoblastic disease  Hydatidiform mole  Multiple gestations  Hydrops Rare  TSH producing pituitary tumour  Iodine induced  Struma ovaii.

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Cause: cross reactivity between hcg and TSH at thyroid receptor
Nausea and vomiting leading to dehydration, electrolyte imbalance and weight loss. Spontaneous resolution by 18 weeks. Antithyroid medications avoided.

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Autoimmune disorder.


Incidence: 0.5%
Most common cause of hyperthyroidism in pregnancy


Symptoms antecedent pregnancy
Physiology: antibodies stimulate thyroid receptors; thyroid hypertrophy and hyperfunction. Antibodies: TPO Thyroglobulin Microsomal Thyroid receptor antibodies.

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Immunoglobulins, ( IgG subclass). 2 types: Stimulating – thyroid stimulating immunoglobulins(TSI); Graves' disease. Blocking – thyrotropin binding inhibitory immunoglobulins(TBII); Hashimoto's thyroiditis.

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Cross the placental barrier

affect fetal thyroid function.

TSI fetal tachycardia, goiter, IUGR, craniosynostosis, premature skeletal maturation, CHF, hydrops. TBII fetal bradycardia, goiter, IUGR.

1st and 2nd trimester
Previous radio-active iodine or thyroidectormy for Graves’ disease New-onset thyrotoxicosis to differentiate Graves’ disease from gestational thyrotoxicosis  Previous pregnancy complicated by fetal or neonatal hyperthyroidism
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3rd trimester

Woman requiring antithyroid drugs for Graves’ disease into third trimester

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Nervousness,Agitation,Fatigue Tachycardia/palpitations Heat intolerance Increased appetite, Weight loss Change in bowel habits Skin/hair/nail changes; Skin is soft and moist Onycholysis (separation of the distal nail from its bed)

Eye signs (distinct from Graves’ ophthalmopathy) Lid lag

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Lid retraction
Proptotis

Hair soft, fine and thin

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Graves' orbitopathy: Chemosis (swelling of the conjunctiva), Proptosis (exophthalmos or bulging orbit), Dysconjugate gaze (double vision on looking to the extremes of the visual field) Pretibial myxedema ( thyroid dermopathy) bilateral, firm, nonpitting, asymmetric plaques or nodules, most often confined to the pretibial area ; may occur anywhere Thyroid bruit Clubbing

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ON PREGNANCY

ON FETUS

Spontaneous abortion,  Preterm birth,  Pre-eclampsia,  Abruption,  Fetal growth restriction,  Perinatal morbidity and mortality,  Congestive heart failure,  Thyroid storm.

Congenital malformations of heart, kidney or brain.  Fetal Graves’ disease  fetal tachycardia,  high output cardiac failure,  NIHF,  craniosynostosis,  LBW,  fetal goiter,  Fetal demise.

Hyperthyroidism can be diagnosed on the basis of

 Clinical presentation

 Thyroid examination
 Thyroid function tests  Thyroid antibody tests

Graves disease- a diffuse, symmetric, soft goiter, which may have an audible bruit. Nodular thyroid disease- A palpable nodule (usually 3 cm) Subacute thyroiditis- generalized thyroid tenderness.

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Goals

To normalize thyroid hormone levels(keeping FT4 in upper normal range <0.85-1.9ng/dl),

To treat bothersome adrenergic symptoms of hyperthyroidism.

Clinical situations:
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Hyperthyroidism under treatment Potential side effects of antithyroid drugs on the fetus discussed. wait 6 months after radioablation. euthyroid at the time of conception. Previous ablation treatment for Graves' disease The dose of thyroid replacement therapy needs to be increased soon after conception. In spite of euthyroidism, high maternal titers for TSI may be present; fetus at risk.
Previous treatment for thyroid carcinoma wait 1 year after completion of radioactive treatment before conception. Inadequately treated hyperthyroidism impaired maturation of the fetal hypothalamic-pituitary-thyroid axis - central congenital hypothyroidism in the infant.

PROPYLTHIOURACIL (PTU)  Inhibits conversion of T4 to T3  Crosses placenta less readily.  Dose- 300-450mg in 3 divided doses of 100-150mg each.  Category D ?
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Improvement seen in 3-4 weeks; full response 8 weeks.

Tapered as pregnancy progresses.

Side effects:

Iatrogenic fetal hypothyroidism Transient leukopenia (10%) Agranulocytosis (0.3-0.4%) Hepatotoxicity (0.1-0.2%) Vasculitis

METHIMAZOLE  Dose- 5–20 mg b.i.d  Crosses placenta more readily.  Category D
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    

Side effects: Transient leukopenia (10%) Agranulocytosis (0.3-0.4%) Hepatotoxicity (0.1-0.2%) Vasculitis

Methimazole embryopathy – Esophageal atresia Choanal atresia Cutis aplasia.

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Dose monitored with 3-4 weekly FT4 or FT4I levels. Improvement seen in 3-4 weeks; full response 8 weeks.

Tapered as pregnancy progresses.

10% fetus exposed to drugs develop fetal or neonatal hypothyroidism

Monitoring:
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Clinical examination for fetal growth
Ultrasonography : FHR (bradycardia) Growth parameters Fetal goiter(symmetric paratracheal mass, neck hyperextension, polyhydramnios)

Cordocentesis.

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Routine fetal blood sampling for thyroid indices is recommended if – previous I131 ablation, Abnormal TSIs or TBII, FGR, heart failure or goiter, with or without tachycardia.

Other drugs in hyperthyroidism
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Beta adrenergic blockers: propranolol. inhibits MOA: T4 T3 20-40mg orally every 8-12 hours

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Management Antithyroid medications, beta-blockers and

Supportive Care.
fetal thyrotoxicosis suspected in labor aggressive treatment of maternal thyrotoxicosis

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fetus with a large goiter

consideration of the best route of delivery

Elective cesarean to avoid dystocia management of the fetal airway.

ex utero intrapartum treatment (EXIT) procedure

Candidates: Fetuses with neck masses large enough to cause airway obstruction ; to manage airway obstruction after fetal surgery.

It involves securing the neonatal airway (usually with endotracheal intubation often guided by laryngoscopy or bronchoscopy) while the umbilical cord and maternal-fetal circulation remain intact in the hopes of avoiding difficult emergency intubations in the delivery room.
Usually perfomed with cesarean deliveries; described with vaginal deliveries too.

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Most commonly diagnosed endocrine malignancy. Incidence: 14 / 1,00,000 pregnant women. Histologic types: papillary, follicular, medullary, Hurthle cell, anaplastic

Papillary thyroid cancer : most common type in pregnancy.
Excellent long term prognosis Surgey delayed postpartum; depending upon histology. S.thyroglobulin : predictive of recurrent disease. Postsurgical I131 whole body scintigraphy and radioiodine remnant ablation : contraindicated in pregnancy & lactation.

CLASSIC FEATURES  Fever,
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PRECIPITATING FACTORS

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Preeclampsia,
Anemia, Sepsis,
surgery.

Tachycardia with atrial fibrillation,

Nausea/vomiting/diarrhoea/ dehydration,
Agitation/delirium/coma,

LAB VALUES


High-output cardiac failure,
Jaundice,

T4 & T3
TLC Transaminases

Abdominal pain.

hypercalcemia

STEP 1. START THIONAMIDES & CONTROL HEART RATE

THIONAMIDES- 1 g PTU (orally or through NG tube) 200 mg every 6 hours

beta-blockers - control tachycardia (maintain HR<90bpm)- propranolol 1-2 mg i/v over 5 min to total of 6-10mg 60–80 mg every 4 hours orally or NG tube.

STEP 2.CORTICOSTEROIDS Dexamethasone 1-2mg PO/IV/IM 6 hourly Or Hydrocortisone 100mg IV 8 hourly Or Prednisone 60mg PO a day

STEP 3.IODINE(after 1-2 hour of thionamide therapy.) SSKI 5 drops orally 8 hourly. Or 500-1000mg sodium iodide i.v. 8 hourly Or Lugol’s solution 10 drops orally 8 hourly Or Lithium carbonate 300mg PO 6 hourly Or Iodinated radiocontrast agents iopodate and iopanoic acid 0.5–1.0 g orally daily.

immunosuppression disappears

postpartum relapse(70%) (within first 3 months)

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TSH and free T4 done 6 weeks post partum. T4 levels must be controlled prior to the next pregnancy.

Drugs in lactating mother:

Both PTU and methimazole excreted in breast milk; PTU is largely protein bound; does not seem to pose a significant risk to the breastfed infant. Methimazole safe only at low doses (10–20 mg/day). AAP and WHO support compatibility of breatfeeding and all antithyroid medications

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Postpartum Rebound in thyroid autoimmunity

lymphocytic infiltration of the thyroid gland

The likelihood of developing postpartum thyroidis is related to serum levels of thyroid autoantibodies. Anti-TPO antibodies are present in 90% of women with PPT.

Women with high antibody titers in early pregnancy have 40–50% chance of developing PPT.
Women with type 1 diabetes have a significantly higher incidence, ranging from 18% to 25% due to the high prevalence of TPO antibodies.

HYPERTHYROID PHASE

HYPOTHYROID PHASE

Autoimmune destruction of the gland - release of stored hormone
1 - 4 months postpartum self-limiting (1–2 months). Abrupt onset fatigue, palpitations, sleep deprivation, nervousness / irritability. small, painless goiter may be present. Antithyroid medications not beneficial.

immune destruction functioning thyrocytes

loss of

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3 - 8 months postpartum (usually at 6 months) lasts much longer (4–6 months) fatigue, weight gain, loss of concentration, depression

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Patients identified with PPT should be screened regularly since 20– 50% of women will develop permanent hypothyroidism within 2–10 years. A TSH level should be done annually and prior to conception.

EVALUATION OF THYROID NODULE IN PREGNANCY Abnormal TSH

Work up & treat Solid lesion>2cm Cystic lesion>4cm <24 weeks

N

USG Solid lesion<2cm Cystic lesion<4cm

>24 weeks Levothyroxine Non malignant Postpartum follow up

FNAC malignant surgery