Hyperthyroid in Pregnancy

Dr. n mohammadi

Fellowship of fetal medicine

Normal physiology

• The hypothalamic pituitary axis • Thyrotropin-releasing hormone (TRH)

– Produced in a tonic fashion in the paraventricular nucleus of the hypothalamus.

• TSH has an α and β subunit;β subunit confers specificity.

• TSH secretion regulated by negative feedback from circulating thyroid hormone, dopamine, and somatostatin.

• TSH then stimulates the thyroid gland to produce, as well as secrete, thyroxine(T4) and triiodothyronine (T3).

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

TSH hCG

• A decrease in basal TSH of 0.1 mU/L was observed for every 10,000 IU/L increment in hCG

• reduction in plasma iodide– fetal :monodeiodinase types II and III in the placenta– increased maternal glomerular filtration rate--

increased renal clearance of iodide throughout pregnancy

• transplacental passage of T4 and iodide and placental metabolism of iodothyronines – stimulate the maternal thyroid ; depleting the maternal

circulation of thyroid hormone and its precursors

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

Screening for Thyroid Disease in Pregnancy

A 24-year-old woman was just diagnosed withher first pregnancy. She enjoys good generalhealth. There is no h/o thyroid disease or Rx.

Q: Should she have screening TFT?

Thyroid 21:1081-1125, 2011

Screening for Thyroid Disease in Pregnancy

Although the benefits of universal screening for thyroid dysfunction may not be justified at this time, selected screening for the following should be done:

• Positive FHxthyroid disease

• Goiter

• TPOAb+

• Symptoms

• Type 1 DM

• Miscarriage

• Other autoimmunedisease

• Infertility

• Morbid obesity

• >30 years

Thyroid 2011

TSH in PregnancyA 28-year-old woman who is 6 weekspregnant has a routine serum TSHlevel of 4.1 mIU/L & FT4 1.3 ng/dL

Q: Is this TSH normal?

Guidelines for Serum TSH During Pregnancy

• Recommendation 1Trimester-specific reference ranges for TSH, as defined in populations with optimal iodine intake,should be applied

• Recommendation 2If trimester-specific reference ranges for TSH are not available in the laboratory, the following references ranges are recommend:1st trimester, 0.1-2.5 mIU/L; 2nd trimester,0.2-3.0 mIU/L; 3rd trimester, 0.3-3.0 mIU/L

Hyperthyroidism and pregnancy

• 0.2% of pregnancies• prevalence 0.1% to 0.4%, with 85% Graves’

disease– Single toxic adenoma, multinodular toxic goiter, and

subacute thyroiditis – gestational trophoblastic disease,viral thyroiditis and

tumors of the pituitary gland or ovary (struma ovarii)

• TSH is depressed and fT4 and fT3 are increased.

• The RT3U that normally is decreased in pregnancy is increased in hyperthyroidism.

Hyperthyroidism and pregnancy

• serum TSH value <0.01 mU/L and also a high serum free T4 value

• may be difficult to determine the cause – thyroid radionuclide imaging is contraindicated in pregnant

women.

• Measurement of thyrotropin receptor antibody (thyroid stimulating immunoglobulins) Graves' disease during pregnancy

• transient hyperthyroidism in hyperemesis gravidarum and gestational transient thyrotoxicity (GTT)

Causes of Low TSH in Pregnancy Trimester 1 2 3 High hCG + - - Gestational Transient Thyrotoxicosis + - - Graves’ Hyperthyroidism + + + Subacute thyroiditis + + + Toxic adenomatous goitre + + + Toxic Multinodular goitre + + + Nodular goitre + + + Mutant TSH Receptor + + + Molar pregnancy + - - TSH assay error + + + Factitious (eg T4 addiction) + + +

Hyperthyroid manifestations

• Nonspecific symptoms;• _Tachycardia• _Heat intolerance• _Increased perspiration

• Additional symptoms: • _Anxiety• _Hand tremor• _Weigh loss despite a normal or increased

appetite

Specific findings:

• Goiter

• ophthalmopathy

Hyperthyroidism and pregnancy

• Severe maternal hyperthyroidism– increased risk of stillbirth – preterm delivery– intrauterine growth restriction – Preeclampsia– heart failure– spontaneous abortion– Fetal thyroid hyperfunction or hypofunction caused by

TSHRAbs – Fetal goiter from excessive antithyroid drug treatment – Neonatal thyrotoxicosis – Increased perinatal and maternal mortality – Decreased IQ of offspring because of excessive use of

antithyroid drugs

Transient hyperthyroidism during pregnancy & gestational transient thyrotoxicity (GTT)

• hyperemesis gravidarum– severe nausea and vomiting leading to a 5% loss of body

weight, dehydration, and ketosis.– absence of goiter and ophthalmopathy, and absence of the common

symptoms and signs of hyperthyroidism

– higher serum hCG and estradiol concentrations – 60% have a subnormal serum TSH level (< 0.4 mU/L),50% have

an elevated serum free T4 concentration– Severity positively correlated with maternal free T4 levels but not

to thyroid function. • 12% elevated free T3 index

– believed to be related to hCG stimulation of the thyroid gland – Normalization of T4 levels by midgestation. – Treatment is supportive care

• GTT– first trimester – related to hCG stimulation of the thyroid gland – symptoms of hyperthyroidism and elevated free T4

levels. – The thyroid gland usually is not enlarged– resolution of symptoms parallels the decline in hCG

levels– usually resolves spontaneously by 20 weeks’

gestation– beyond 20 weeks,repeat evaluation for other causes

Trophoblastic hyperthyroidism

• hydatidiform mole (molar pregnancy) & choriocarcinoma. – high serum hCG concentrations and abnormal hCG

isoforms

• 55 to 60 percent had clinically evident hyperthyroidism

• normal thyroid gland and few symptoms of thyroid hormone excess.

• some :findings of hyperthyroidism and a diffuse goiter– ophthalmopathy is not present

• Nausea and vomiting may predominate

Trophoblastic hyperthyroidisem

• Women with symtomatic moderate to severe hyperthyroidisem due to trophoblastic diseases require treatment.

• This include women with total T4 and total T3> 1.5 times the upper limit of nonpregnant women, require antithyroid therapy.

subclinical hyperthyroidism

• Low TSH and normal free T4.

• associated with osteoporosis cardiovascular morbidity, and progression to overt thyrotoxicosis and thyroid failure.

• not associated with adverse pregnancy outcomes

• does not warrant treatment.

Graves’ disease

• 95% of thyrotoxicosis during pregnancy. • activity level fluctuate during gestation, with

– exacerbation during the first trimester– gradual improvement during the latter half. – exacerbation shortly after delivery

• clinical scenarios.– stable Graves’ disease receiving thionamide therapy

with exacerbation during early pregnancy. – in remission with a relapse of disease. – without prior history diagnosed with Graves’ disease d

e novo during pregnancy.

Graves’ disease

• Diagnosis– difficult :hypermetabolic symptoms in normal

pregnancy– thyroid examination: goiter (with or without bruit) – suppressed serum TSH level and usually elevated

free and total T4 serum concentrations.– TSH receptor antibodi

• autoantibodies mimic TSH can cross the placenta and cause neonatal Graves’ disease

Graves’ disease

• Pregnancy outcome• preterm labor

– untreated (88%)/partially treated(25%) /adequately treated (8%) [• preeclampsia

– untreated twice • stillbirth

– untreated (50%) /partially treated (16%) /adequately treated (0%) • small for gestational age • congenital malformations unrelated to thionamide therapy• Mother may have thyroid-stimulating hormone-binding inhibitory

immunoglobulin (TBII), – cause transient neonatal hypothyroidism – fetal bradycardia, goiter,and growth restriction

Graves’ disease• Neonatal thyrotoxicosis :

– 1% of infants – occur in euthyroid mother or has had surgical or radioactive

131I treatments before pregnancy– fetal ultrasound to exclude evidence of fetal thyrotoxicosis

(eg, an anterior fetal neck mass) or fetal tachycardia. – fetal goiter, advanced bone age, poor growth, and

craniosynostosis, Cardiac failure and hydrops – Fetal blood sampling — Fetal blood for thyroid function

tests by percutaneous umbilical vein sampling after 20 weeks of gestation

• High maternal TSH receptor-stimulating antibody levels Fetal signs suggestive of thyroid disease History of a prior baby with hyperthyroidism

Thyroid storm

• obstetric emergency • extreme metabolic state• 10% of pregnant women with hyperthyroidism• high risk of maternal cardiac failure.• fever, change in mental status, seizures, nausea,

diarrhea, and cardiac arrhythmias.• inciting event (eg, infection, surgery, labor/delivery) and

a source of infection • treatment immediately, even if serum free T4, free T3,

and TSH levels are not known. • untreated thyroid storm can be shock, stupor, and coma.

Guidelines for clinical management of maternalhyperthyroidism during pregnancy

• 1. Use the lowest dosage of thionamide (preferably PTU) to maintain maternal total T4 concentrations in the upper one third of normal to slightly elevated range for pregnancy.– Normal range of total T4 during pregnancy is

estimated to be 1.5 times the nonpregnant state

• 2. Monitor maternal total T4 serum concentration every 2–4 weeks, and titrate thionamide as necessary. – Monitoring serum TSH may become useful later.

Guidelines for clinical management of maternalhyperthyroidism during pregnancy

• 3. Measure TSH receptor antibodies (thyroid-stimulating immunoglobulins or TSH receptor binding inhibitory immunoglobulins) at 26–28 weeks to assess risk of fetal/neonatal hyperthyroidism. – TSH receptor antibody measurement is crucial in

hypothyroid levothyroxine-treated women with a prior history of Graves’ disease, who do not appear thyrotoxic.

• 4. Perform fetal ultrasound at weeks 26–28 to assess potential fetal response to thionamide treatment and effect of TSH receptor antibodies on fetal thyroid function

Treatment • Thionamides• propylthiouracil (PTU) and methimazole(MMI)• Both cross the placenta with equal transfer

kinetics.• Both can cause fetal goiter and hypothyroidism,

usually mild and transient & dose-dependent • median time to normalization of maternal thyroid

function– 7 weeks with PTU and 8 weeks with MMI

• PTU more highly bound to albumin – theorize that MMI crosses the placenta in higher

concentrations

Treatment

• Thionamides• maternal :rash• rare birth defects in MMI: aplasia cutis, choanal

atresia,esophageal atresia, and minor dysmorphic features• Low thyroid function at birth ½ neonates whose mothers received PTU or MMI

and had serum T4 concentrations within the normal (non-pregnant) range– normal IQ scores

• Graves’ disease may ameliorate – thionamide discontinued in 30% during the final weeks– fall in serum TSH receptor-stimulating antibody concentrations and a rise

in TSH receptor-blocking antibodies. • Graves' hyperthyroidism can worsen postpartum • do not recommend the use of T4 with thionamide therapy during

pregnancy.

Treatment

• β-Adrenergic blockers• weaned as soon as the hyperthyroidism is controlled • occasional cases of neonatal growth restriction,

hypoglycemia, respiratory depression, and bradycardia • increased frequency of first-trimester miscarriages • avoiding in the first trimester

• Iodides• past reports of neonatal hypothyroidism after exposure to

iodine • low-dose potassium iodide may be considered

– Preparation for thyroidectomy – thionamide-intolerant patients refusing surgery.

Treatment

• Surgery• Subtotal thyroidectomy :

– persistently high dosages of thionamides (PTU > 600 mg/d, MMI > 40 mg/d) are required to control maternal disease

– allergic or intolerant of both thionamides– noncompliant with medical therapy– compressive symptoms

• second trimester, before gestational week 24• prepared with a β-adrenergic blocking agent and a 10- to 14-day

course of potassium iodide

Treatment

• Radioactive iodine therapy• contraindicated • fetal thyroid gland begins to concentrate iodine after

gestational week 10, Fetal thyroid tissue is present by 10 to 12 weeks – predisposing to congenital hypothyroidism

• Nursing • Breast feeding in mothers taking PTU or MMI is safe • Thyroid function in newborn infants is unaffected • PTU is preferred because it is less concentrated in breast

milk

Up to date_ATA

• Suggest that PTU use be limited to first trimester only.

• In the second trimester,switching from PTU to MMI

• Initial lowest dose: PTU 50 mg two or three times daily and MMI 5 to 10 mg daily.

PTU associated liver failure:

• Sudden onset- rapidly progressive

• Routine monitoring of LFT is not recommended.

• Malaise weakness nausea vomiting jundice dark urine light-colored stools.

A 32-year-old woman pregnant 10 weeks presents with nausea, vomiting, and a 2 kg weight loss; her first pregnancy 2 years earlier was uncomplicated

On exam she is dehydrated, euthyroid, without a goiter and has normal eyes

TSH 0.01 (<2.5)FT4 2.1 (0.8-1.8)FT4I 20 (5-12)

Q: Does she require antithyroid Rx?

Hyperthyroidism & PregnancyConclusions

• Hyperemesis gravidarum is HCG-induced, reversible, and dosent requires ATD.

• Measure TSH receptor Ab (TRAb),TBII assay

• and TOTAL T3 to distinguish from Graves’ disease.

Hyperthyroidism & Pregnancy

• Recommendation 22When serum TSH is suppressed (<0.1) inthe 1st trimester, FT4 should be obtained;TT3 & TRAb may also be helpful

• Recommendation 26ATDs are not recommended for Rx of gestational hyperthyroidism

Hyperthyroidism & Pregnancy

A 32-year-old woman is 8 weeks pregnant; she reports palpitations, anxiety, heat intolerance and an 8 lb weight loss for 6 months

On exam she is nervous, slightly hyperthyroid, has lid lag, and thyroid is x2 enlarged

TSH 0.01FT4 2.8FT4I 16 (5-12)TRAb 75% (<16%)

Q: How do you manage?

Postpartum thyroid disease

• Postpartum thyroiditis– Dx: documenting abnormal TSH (elevated or

suppressed) levels during the first year postpartum in the absence of positive TSI or a toxic nodule

– hypo- or hyperthyroidism– classic presentation :– transient hyperthyroid phase that occurs 6 weeks to 6

months postpartum– followed by a hypothyroid phase that lasts for up to 1

year postpartum

Postpartum thyroiditis• autoimmune disorder with a self-limited hyperthyroid phase• within one year after parturition. • Presentations

– Transient hyperthyroidism alone – Transient hypothyroidism alone – Transient hyperthyroidism followed by hypothyroidism

and then recovery. • can also occur after spontaneous or induced

abortion • 3 to 16 percent

– higher, up to 25 percent, in women with type 1 diabetes mellitus ,and in women with positive antithyroid antibodies (normal thyroid function)

Postpartum thyroiditis• like painless thyroiditis

– variant form of chronic autoimmune thyroiditis (Hashimoto's thyroiditis). • high serum concentrations of anti-peroxidase antibodies • many eventually become hypothyroid or have a goiter • high serum antithyroid antibody concentrations early in pregnancy

– decline later (as immunologic tolerance increases during pregnancy) – rise again after delivery

• subclinical thyroid autoimmune disease early in pregnancy and soon after

• Progression to permanent hypothyroidism – related to higher TSH concentrations and the antiperoxidase antibody

titer – maternal age and female sex of the infant

• Postpartum thyroiditis is likely to recur after subsequent pregnancies

• distinguished from Graves' hyperthyroidism, – hyperthyroidism in postpartum thyroiditis is usually

mild (both clinically and biochemically), – thyroid enlargement is minimal– Graves' ophthalmopathy is absent. – by reevaluation in three to four weeks: postpartum

thyroiditis improved

• lymphocytic hypophysitis,– TSH normal or low, low free T4 – postpartum thyroiditis, TSH elevated with decreased

FT4.

Postpartum thyroiditis

• antithyroids :no role. • Hypothyroid :may require treatment and some • significant rate of residual hypothyroidism

– Recommend:maintain thyroxine until childbearing is complete, with an attempt to wean off medication 1 year after the last delivery

• Postpartum--signs/symptoms of thyroid dysfunction – symptoms mimic normal postpartum changes

• TSH, free T4, and antithyroid antibodies levels • postpartum depression and postpartum thyroiditis

Postpartum Graves’ disease

• 60% Graves’ disease in the reproductive years; postpartum onset

• euthyroid patients with Graves’ disease with TSI – increased risk of developing recurrent Graves’

disease if antithyroid medication was withheld

• TSIs differentiate postpartum Graves’ disease from postpartum thyroiditis with a hyperthyroid component.

Thyroid cancer

• Thyroid tumors ;most common endocrine neoplasms. • thyroid cancer accounts for 1% of all cancers. ¾ women; 1/2

reproductive years.• biopsy ,Serum TSH and free T4 levels,ultrasonography & Fine

needle aspiration • Radionucleotide scanning is contraindicated during pregnancy• malignant or suspicious for papillary cancer, surgery at the earliest

safe period• no evidence that pregnancy causes a reactivation of thyroid cancer

or that exposure to radioactive iodine poses a risk to future pregnancies

• maintained on thyroid replacement therapy with monitoring of TSH and free T4 levels every 8 weeks.

Euthyroidism with autoimmune thyroid disease

• increased risk for spontaneous miscarriage, subclinical hypothyroidism, and postpartum thyroiditis

• Increase in serum TSH levels– most normal

• presence of antithyroid antibodies – lack of thyroidal reserve in response to the

stimulatory effects of pregnancy.

Euthyroidism with autoimmune thyroid disease

• recommend initiating levothyroxine therapy in women with antithyroid antibodies – before pregnancy– TSH level greater than 2.5 mU/L.

• Serum TSH should be monitored throughout pregnancy in all antithyroid antibody–positive women

• maintain the TSH concentration at 2.5 mU/L or less.

CLINICAL PRACTICE GUIDELINEManagement of Thyroid Dysfunction during Pregnancy

and Postpartum: An Endocrine Society ClinicalPractice Guideline

• 1. HYPOTHYROIDISM AND PREGNANCY: MATERNAL• AND FETAL ASPECTS• 1.1.1. maternal hypothyroidism should be avoided.Targeted case

finding is recommended at the first prenatalvisit or at diagnosis of pregnancy

• 1.1.2. If hypothyroidism diagnosed before pregnancy, adjust preconception T4 dose to reach a TSH ≤2.5 U/ml before pregnancy.

• 1.1.3. T4 dose incremented by 4–6 wk gestation and 30–50% increase in dosage.

• 1.1.4. If overt hypothyroidism is diagnosed during pregnancy, thyroid function tests should be normalized as rapidly as possible. – The T4 dosage should be titrated to rapidly ,maintain serum TSH ≤ 2.5

U/ml in the first trimester (or 3 U/ml in the second and third trimesters) or to trimester-specific normal TSH ranges.

– Thyroid function tests remeasured within 30–40 d.

• 1.1.5. Women with thyroid autoimmunity who are euthyroid in the early stages of pregnancy are at risk of developing hypothyroidism and should be monitored for elevation of TSH above the normal range

• 1.1.6. Subclinical hypothyroidism ;associated with an• adverse outcome for both the mother and offspring.

– T4 treatment - improve obstetrical outcome but has not been proved to modify long-term neurological development in the offspring.

– Recommends T4 replacement in women with subclinical hypothyroidism.

• 1.1.7. After delivery, most hypothyroid women need a• decrease in the T4 dosage they received during

pregnancy

• 3. GESTATIONAL HYPEREMESIS AND HYPERTHYROIDISM

• 3.1. Thyroid function tests should be measured in all patients with hyperemesis gravidarum (5% weight loss, dehydration, and ketonuria)

• 3.2. Few women with hyperemesis gravidarum will require ATD treatment.

• Overt hyperthyroidism believed due to coincident Graves’ disease should be treated with ATD.

• Gestational hyperthyroidism with clearly elevated thyroid hormone levels (free T4 above the reference range or total T4 150% of top normal pregnancy value and TSH 0.1 U/ml) and evidence of hyperthyroidism may require treatment as long as clinically necessary

• 4. AUTOIMMUNE THYROID DISEASE AND MISCARRIAGE

• 4.1. universal screening for antithyroid antibodies and possible treatment cannot be recommended at this time.

• 6. IODINE NUTRITION DURING PREGNANCY• 6.1. Women of childbearing age ; average iodine intake 150 g/d. • pregnancy and breastfeeding women should increase intake to 250

g • 6.2. Iodine intake during pregnancy and breastfeeding should not

exceed twice the daily recommended nutritional intake for iodine, i.e. 500 g iodine per day

• 6.3. To assess the adequacy of the iodine intake during pregnancy in a population, urinary iodine concentration should be measured in a cohort of the population. – Urinary iodine concentration should ideally range between 150 and 250

g/liter. • 6.4. To reach the daily recommended nutrient intake for iodine,

multiple means must be considered, tailored to the iodine intake level in a given population. – 1) countries with iodine sufficiency and/or with a well established

universal salt iodization (USI) program, – 2) countries without a USI program or an established USI program

where the coverage is known to be only partial, and finally – 3) remote areas with no accessible USI program and difficult

socioeconomic conditions.

• 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.

• 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.